Compounds and methods for modulating scn2a

ABSTRACT

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of SCN2A RNA in a cell or subject, and in certain instances reducing the amount of SCN2A protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a disease or disorder associated with a voltage-gated sodium channel protein, such as, for example, a Developmental and Epileptic Encephalopathy, an intellectual disability, or an autism spectrum disorder. Such symptoms and hallmarks include, but are not limited to seizures, hypotonia, sensory integration disorders, motor development delays and dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, visual dysfunctions, delayed language and speech, gastrointestinal disorders, neurodevelopmental delays, sleep problems, and sudden unexpected death in epilepsy.

SEQUENCE LISTING

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BIOL0373WOSEQ_ST25.txt, created on Aug. 2, 2021, which is 850 KB in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

FIELD

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of SCN2A RNA in a cell or subject, and in certain instances reducing the amount of SCN2A protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a disease or disorder associated with a voltage-gated sodium channel protein, such as, for example, a Developmental and Epileptic Encephalopathy, an intellectual disability, or an autism spectrum disorder. Such symptoms and hallmarks include, but are not limited to seizures, hypotonia, sensory integration disorders, motor development delays and dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, visual dysfunctions, delayed language and speech, gastrointestinal disorders, neurodevelopmental delays, sleep problems, and sudden unexpected death in epilepsy.

BACKGROUND

The human gene SCN2A encodes human SCN2A protein, the alpha-1 subunit of the voltage-gated sodium channel NaV1.2. Mutations in SCN2A are associated with a variety of neurodevelopmental and intellectual diseases and disorders, such as Developmental and Epileptic Encephalopathies (DEE), including Early Seizure Onset Epileptic Encephalopathy (EE), Late Seizure Onset Epileptic Encephalopathy, and Benign Familial Neonatal-Infantile Seizures (BFNIS); mutations in SCN2A are also associated with intellectual disability (ID) and/or autism spectrum disorder (ASD), with or without seizures (Wolff, M., et al., 2019, Epilepsia 60, S59-S67; Sanders, S., et al., 2018, Trends in Neurosciences 41, 442-456; Wolff, M., et al., 2017, Brain 140, 1316-1336). DEEs include abroad range of diseases that include neonatal and early infantile DEE, for example Ohtahara Syndrome and epilepsy with migrating focal seizures of infancy (EIMFS); infantile and childhood DEE, for example West Syndrome and Lennon-Gastaut Syndrome; Dravet Syndrome; Idiopathic/Generic Generalized Epilepsies (IGE/GGE); Temporal Lobe Epilepsy; Myoclonic Astatic Epilepsy (MAE); Migrating Partial Epilepsy of Infancy (MMPSI); and familial hemiplegic migraines, with or without epilepsy (Wolff, M., et al., 2019; Harkin, L. A., et al., 2007, Brain 130, 843-852; Escayg, A., et al., 2010, Epilepsia 51, 1650-1658; Miller I. O, et al., 2007 Nov. 29 [Updated 2019 Apr. 18]. In: Adam M P, Ardinger H H, Pagon R A, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: www.ncbi.nlm.nih.gov/books/NBK1318/).

Symptoms and hallmarks associated with DEEs include seizures, hypotonia, sensory integration disorders, motor development delays and dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, visual dysfunctions, delayed language and speech, gastrointestinal disorders, neurodevelopmental delays, sleep problems, and sudden unexpected death in epilepsy. Seizures include focal, clonic, tonic, and generalized tonic and clonic seizures, prolonged seizures (often lasting longer than 10 minutes), and frequent seizures (for example, convulsive, myoclonic, absence, focal, obtundation status, and tonic seizures) (Guzzetta, F., 2011, Epilepsia 52:S2, 35-38; Anwar et al., 2019, Cureus 11, e5006, Wolff et al., 2019). Symptoms and hallmarks associated with ID and ASD include motor development delays, delayed social and language milestones, repetitive actions, uncoordinated oral movements, gastrointestinal disorders, sleep problems, and seizures (Wolff et al., 2019).

Currently there is a lack of acceptable options for treating DEEs such as EEs, Late Onset EEs, and BFNIS; and for treating ID and ASD. It is therefore an object herein to provide compounds, methods, and pharmaceutical compositions for the treatment of such diseases and disorders.

SUMMARY OF THE INVENTION

Provided herein are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of SCN2A RNA, and in certain embodiments reducing the expression of SCN2A protein in a cell or subject. In certain embodiments, the subject has a disease or disorder associated with a voltage-gated sodium channel protein. In certain embodiments, the voltage-gated sodium channel protein is SCN2A. In certain embodiments, the subject has a disease or disorder associated with a voltage-gated sodium channel protein that is not SCN2A. In certain embodiments, the subject has a disease or disorder associated with SCN1A.

In certain embodiments, the subject has a Developmental or Epileptic Encephalopathy; in certain embodiments, the subject has Early Seizure Onset Epileptic Encephalopathy; in certain embodiments, the subject has Late Seizure Onset Epileptic Encephalopathy; in certain embodiments the subject has Benign Familial Neonatal-Infantile Seizures; in certain embodiments, the subject has an intellectual disability (ID); in certain embodiments, the subject has an autism spectrum disorder (ASD); in certain embodiments, the subject has Dravet Syndrome. In certain embodiments, compounds useful for reducing the amount or activity of SCN2A RNA are oligomeric compounds. In certain embodiments, compounds useful for reducing the amount or activity of SCN2A RNA are modified oligonucleotides. In certain embodiments, compounds useful for reducing expression of SCN2A protein are oligomeric compounds. In certain embodiments, compounds useful for reducing expression of SCN2A protein are modified oligonucleotides.

Also provided are methods useful for ameliorating at least one symptom or hallmark of a Developmental or Epileptic Encephalopathy such as EEs, Late Seizure Onset EEs, and BFNIS; an intellectual disability; or autism spectrum disorder. In certain embodiments, the symptom or hallmark includes seizures, hypotonia, sensory integration disorders, motor dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, visual dysfunctions, delayed language and speech, neurodevelopmental delays, sudden unexpected death in epilepsy, motor development delays, delayed social and language milestones, repetitive actions, uncoordinated oral movements, gastrointestinal disorders (for example, gastroesophageal reflux, diarrhea, constipation, dysmotility, and the like), and sleep problems. In certain embodiments, the seizures include focal, clonic, tonic, and generalized tonic and clonic seizures, prolonged seizures (often lasting longer than 10 minutes), and frequent seizures (for example, convulsive, myoclonic, absence, focal, obtundation status, and tonic seizures).

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included,” is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, treatises, and GenBank, ENSEMBL, and NCBI reference sequence records are hereby expressly incorporated-by-reference for the portions of the document discussed herein, as well as in their entirety.

Definitions

Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Where permitted, all patents, applications, published applications and other publications and other data referred to throughout in the disclosure are incorporated by reference herein in their entirety.

Unless otherwise indicated, the following terms have the following meanings:

Definitions

As used herein, “2′-deoxynucleoside” means a nucleoside comprising a 2′-H(H) deoxyfuranosyl sugar moiety. In certain embodiments, a 2′-deoxynucleoside is a 2′-β-D-deoxynucleoside and comprises a 2′-β-D-deoxyribosyl sugar moiety, which has the β-D ribosyl configuration as found in naturally occurring deoxyribonucleic acids (DNA). In certain embodiments, a 2′-deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (uracil).

As used herein, “2′-MOE” means a 2′-OCH₂CH₂OCH₃ group in place of the 2′—OH group of a furanosyl sugar moiety. A “2′-MOE sugar moiety” means a sugar moiety with a 2′-OCH₂CH₂OCH₃ group in place of the 2′—OH group of a furanosyl sugar moiety. Unless otherwise indicated, a 2′-MOE sugar moiety is in the β-D-ribosyl configuration. “MOE” means O-methoxyethyl.

As used herein, “2′-MOE nucleoside” means a nucleoside comprising a 2′-MOE sugar moiety.

As used herein, “2′-OMe” means a 2′-OCH₃ group in place of the 2′—OH group of a furanosyl sugar moiety. A “2′-O-methyl sugar moiety” or “2′-OMe sugar moiety” means a sugar moiety with a 2′-OCH₃ group in place of the 2′-OH group of a furanosyl sugar moiety. Unless otherwise indicated, a 2′-OMe sugar moiety is in the β-D-ribosyl configuration.

As used herein, “2′-OMe nucleoside” means a nucleoside comprising a 2′-OMe sugar moiety.

As used herein, “2′-substituted nucleoside” means a nucleoside comprising a 2′-substituted sugar moiety. As used herein, “2′-substituted” in reference to a sugar moiety means a sugar moiety comprising at least one 2′-substituent group other than H or OH.

As used herein, “5-methyl cytosine” means a cytosine modified with a methyl group attached to the 5 position. A 5-methyl cytosine is a modified nucleobase.

As used herein, “administering” means providing a pharmaceutical agent to a subject.

As used herein, “antisense activity” means any detectable and/or measurable change attributable to the hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity is a decrease or reduction in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the antisense compound.

As used herein, “antisense compound” means an oligomeric compound capable of achieving at least one antisense activity. An antisense compound comprises an antisense oligonucleotide and optionally one or more additional features, such as a conjugate group.

As used herein, “antisense agent” means an antisense compound and optionally one or more additional features, such as a sense compound.

As used herein, “sense compound” means a sense oligonucleotide and optionally one or more additional features, such as a conjugate group.

As used herein, “antisense oligonucleotide” means an oligonucleotide, including the oligonucleotide portion of an antisense compound, that is capable of hybridizing to a target nucleic acid and is capable of at least one antisense activity. Antisense oligonucleotides include but are not limited to antisense RNAi oligonucleotides and antisense RNase H oligonucleotides.

As used herein, “ameliorate” in reference to a treatment means improvement in at least one symptom or hallmark relative to the same symptom or hallmark in the absence of the treatment. In certain embodiments, amelioration is the reduction in the severity or frequency of a symptom or hallmark or the delayed onset or slowing of progression in the severity or frequency of a symptom or hallmark. In certain embodiments, the symptom or hallmark is seizures, hypotonia, sensory integration disorders, motor dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, visual dysfunctions, delayed language and speech, neurodevelopmental delays, sudden unexpected death in epilepsy, motor development delays, delayed social and language milestones, repetitive actions, uncoordinated oral movements, gastrointestinal disorders (for example, gastroesophageal reflux, diarrhea, constipation, dysmotility, and the like), or sleep problems. In certain embodiments, the seizures are focal, clonic, tonic, and generalized tonic and clonic seizures, prolonged seizures (often lasting longer than 10 minutes), or frequent seizures (for example, convulsive, myoclonic, absence, focal, obtundation status, or tonic seizures).

As used herein, “bicyclic sugar” or “bicyclic sugar moiety” means a modified sugar moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In certain embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety. In certain embodiments, the furanosyl sugar moiety is a ribosyl moiety. In certain embodiments, the bicyclic sugar moiety does not comprise a furanosyl moiety.

As used herein, “bicyclic nucleoside” or “BNA” means a nucleoside comprising a bicyclic sugar moiety.

As used herein, “cerebrospinal fluid” or “CSF” means the fluid filling the space around the brain and spinal cord. “Artificial cerebrospinal fluid” or “aCSF” means a prepared or manufactured fluid that has certain properties of cerebrospinal fluid.

As used herein, “cleavable moiety” means a bond or group of atoms that is cleaved under physiological conditions, for example, inside a cell, an animal, or a human.

As used herein, “complementary” in reference to an oligonucleotide means that at least 70% of the nucleobases of the oligonucleotide or one or more portions thereof and the nucleobases of a another nucleic acid or one or more portions thereof are capable of hydrogen bonding with one another when the nucleobase sequence of the oligonucleotide and the other nucleic acid are aligned in opposing directions. As used herein, complementary nucleobases means nucleobases that are capable of forming hydrogen bonds with one another. Complementary nucleobase pairs include adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), 5-methyl cytosine (mC) and guanine (G). Complementary oligonucleotides and/or target nucleic acids need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated. As used herein, “fully complementary” or “100% complementary” in reference to an oligonucleotide, or a portion thereof, means that the oligonucleotide, or portion thereof, is complementary to another oligonucleotide or target nucleic acid at each nucleobase of the shorter of the two oligonucleotides, or at each nucleoside if the oligonucleotides are the same length.

As used herein, “conjugate group” means a group of atoms that is directly or indirectly attached to an oligonucleotide. Conjugate groups include a conjugate moiety and a conjugate linker that attaches the conjugate moiety to the oligonucleotide.

As used herein, “conjugate linker” means a single bond or a group of atoms comprising at least one bond that connects a conjugate moiety to an oligonucleotide.

As used herein, “conjugate moiety” means a group of atoms that is attached to an oligonucleotide via a conjugate linker.

As used herein, “contiguous” in the context of an oligonucleotide refers to nucleosides, nucleobases, sugar moieties, or internucleoside linkages that are immediately adjacent to each other. For example, “contiguous nucleobases” means nucleobases that are immediately adjacent to each other in a sequence.

As used herein, “cEt” means a 4′ to 2′ bridge in place of the 2′OH-group of a ribosyl sugar moiety, wherein the bridge has the formula of 4′-CH(CH₃)—O-2′, and wherein the methyl group of the bridge is in the S configuration. A “cEt sugar moiety” is a bicyclic sugar moiety with a 4′ to 2′ bridge in place of the 2′OH-group of a ribosyl sugar moiety, wherein the bridge has the formula of 4′-CH(CH₃)—O-2′, and wherein the methyl group of the bridge is in the S configuration. “cEt” means constrained ethyl.

As used herein, “cEt nucleoside” means a nucleoside comprising a cEt modified sugar moiety.

As used herein, “chirally enriched population” means a plurality of molecules of identical molecular formula, wherein the number or percentage of molecules within the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules expected to contain the same particular stereochemical configuration at the same particular chiral center within the population if the particular chiral center were stereorandom. Chirally enriched populations of molecules having multiple chiral centers within each molecule may contain one or more stereorandom chiral centers. In certain embodiments, the molecules are modified oligonucleotides. In certain embodiments, the molecules are compounds comprising modified oligonucleotides.

As used herein, “chirally controlled” in reference to an internucleoside linkage means chirality at that linkage is enriched for a particular stereochemical configuration.

As used herein, “deoxy region” means a region of 5-12 contiguous nucleotides, wherein at least 70% of the nucleosides are 2′-β-D-deoxynucleosides. In certain embodiments, each nucleoside is selected from a 2′-β-D-deoxynucleoside, a bicyclic nucleoside, and a 2′-substituted nucleoside. In certain embodiments, a deoxy region supports RNase H activity. In certain embodiments, a deoxy region is the gap or internal region of a gapmer.

As used herein, “gapmer” means a modified oligonucleotide comprising an internal region having a plurality of nucleosides that support RNase H cleavage positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions. The internal region may be referred to as the “gap” and the external regions may be referred to as the “wings” or “wing segments.” In certain embodiments, the internal region is a deoxy region. The positions of the internal region or gap refer to the order of the nucleosides of the internal region and are counted starting from the 5′-end of the internal region. Unless otherwise indicated, “gapmer” refers to a sugar motif. In certain embodiments, each nucleoside of the gap is a 2′-β-D-deoxynucleoside. In certain embodiments, the gap comprises one 2′-substituted nucleoside at position 1, 2, 3, 4, or 5 of the gap, and the remainder of the nucleosides of the gap are 2′-β-D-deoxynucleosides. As used herein, the term “MOE gapmer” indicates a gapmer having a gap comprising 2′-β-D-deoxynucleosides and wings comprising 2′-MOE nucleosides. As used herein, the term “mixed wing gapmer” indicates a gapmer having wings comprising modified nucleosides comprising at least two different sugar modifications. Unless otherwise indicated, a gapmer may comprise one or more modified internucleoside linkages and/or modified nucleobases and such modifications do not necessarily follow the gapmer pattern of the sugar modifications.

As used herein, “hotspot region” is a range of nucleobases on a target nucleic acid that is amenable to oligomeric compound-mediated reduction of the amount or activity of the target nucleic acid.

As used herein, “hybridization” means the pairing or annealing of complementary oligonucleotides and/or nucleic acids. While not limited to a particular mechanism, the most common mechanism of hybridization involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases.

As used herein, “internucleoside linkage” means the covalent linkage between contiguous nucleosides in an oligonucleotide. As used herein, “modified internucleoside linkage” means any internucleoside linkage other than a phosphodiester internucleoside linkage. “Phosphorothioate internucleoside linkage” or “PS internucleoside linkage” is a modified internucleoside linkage in which one of the non-bridging oxygen atoms of a phosphodiester internucleoside linkage is replaced with a sulfur atom.

As used herein, “linker-nucleoside” means a nucleoside that links, either directly or indirectly, an oligonucleotide to a conjugate moiety. Linker-nucleosides are located within the conjugate linker of an oligomeric compound. Linker-nucleosides are not considered part of the oligonucleotide portion of an oligomeric compound even if they are contiguous with the oligonucleotide.

As used herein, “LNA” means locked nucleic acid. An “LNA sugar moiety” is a bicyclic sugar moiety with a 4′ to 2′ bridge in place of the 2′OH-group of a furanosyl sugar moiety, wherein the bridge has the formula of 4′-CH₂—O-2′. “LNA” means locked nucleic acid. In some embodiments, the furanosyl sugar moiety is a ribosyl sugar moiety. As used herein, “LNA nucleoside” means a nucleoside comprising a LNA sugar moiety.

As used herein, “non-bicyclic modified sugar moiety” means a modified sugar moiety that comprises a modification, such as a substituent, that does not form a bridge between two atoms of the sugar to form a second ring.

As used herein, “mismatch” or “non-complementary” means a nucleobase of a first oligonucleotide that is not complementary with the corresponding nucleobase of a second oligonucleotide or target nucleic acid when the first and second oligonucleotide are aligned.

As used herein, “motif” means the pattern of unmodified and/or modified sugar moieties, nucleobases, and/or internucleoside linkages, in an oligonucleotide.

As used herein, “nucleobase” means an unmodified nucleobase or a modified nucleobase. As used herein an “unmodified nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G). As used herein, a “modified nucleobase” is a group of atoms other than unmodified A, T, C, U, or G capable of pairing with at least one unmodified nucleobase. A “5-methyl cytosine” is a modified nucleobase. A universal base is a modified nucleobase that can pair with any one of the five unmodified nucleobases. As used herein, “nucleobase sequence” means the order of contiguous nucleobases in a target nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage modification.

As used herein, “nucleoside” means a compound or a fragment of a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. As used herein, “modified nucleoside” means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase. “Linked nucleosides” are nucleosides that are connected in a contiguous sequence (i.e., no additional nucleosides are presented between those that are linked).

As used herein, “oligomeric compound” means an oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group. An oligomeric compound may be paired with a second oligomeric compound that is complementary to the first oligomeric compound or may be unpaired. A “singled-stranded oligomeric compound” is an unpaired oligomeric compound. The term “oligomeric duplex” means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may be referred to as a “duplexed oligomeric compound.”

As used herein, “oligonucleotide” means a strand of linked nucleosides connected via internucleoside linkages, wherein each nucleoside and internucleoside linkage may be modified or unmodified. Unless otherwise indicated, oligonucleotides consist of 8-50 linked nucleosides. As used herein, “modified oligonucleotide” means an oligonucleotide, wherein at least one nucleoside or internucleoside linkage is modified. As used herein, “unmodified oligonucleotide” means an oligonucleotide that does not comprise any nucleoside modifications or internucleoside modifications.

As used herein, “pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to a subject. Certain such carriers enable pharmaceutical compositions to be formulated as, for example, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspension and lozenges for the oral ingestion by a subject. In certain embodiments, a pharmaceutically acceptable carrier or diluent is sterile water, sterile saline, sterile buffer solution or sterile artificial cerebrospinal fluid.

As used herein, “pharmaceutically acceptable salts” means physiologically and pharmaceutically acceptable salts of compounds. Pharmaceutically acceptable salts retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.

As used herein, “pharmaceutical composition” means a mixture of substances suitable for administering to a subject. For example, a pharmaceutical composition may comprise an oligomeric compound and a sterile aqueous solution. In certain embodiments, a pharmaceutical composition shows activity in free uptake assay in certain cell lines.

As used herein, “prodrug” means a therapeutic agent in a form outside the body that is converted to a different form within a subject or cells thereof. Typically, conversion of a prodrug within the subject is facilitated by the action of an enzymes (e.g., endogenous or viral enzyme) or chemicals present in cells or tissues and/or by physiologic conditions.

As used herein, “reducing the amount,” “reducing the activity,” “decreasing the amount,” or “decreasing the activity” refers to a reduction or blockade of the transcriptional expression or activity relative to the transcriptional expression or activity in an untreated or control sample and does not necessarily indicate a total elimination of transcriptional expression or activity.

As used herein, “RNA” means an RNA transcript and includes pre-mRNA and mature mRNA unless otherwise specified.

As used herein, “RNAi compound” means an antisense compound that acts, at least in part, through RISC or Ago2 to modulate a target nucleic acid and/or protein encoded by a target nucleic acid. RNAi compounds include, but are not limited to double-stranded siRNA, single-stranded RNA (ssRNA), and microRNA, including microRNA mimics. In certain embodiments, an RNAi compound modulates the amount, activity, and/or splicing of a target nucleic acid. The term RNAi compound excludes antisense compounds that act through RNase H.

As used herein, “self-complementary” in reference to an oligonucleotide means an oligonucleotide that at least partially hybridizes to itself.

As used herein, “standard in vitro assay” means the assay described in Example 1 and reasonable variations thereof.

As used herein, “standard in vivo assay” means the assay described in Example 8 and reasonable variations thereof.

As used herein, “stereorandom chiral center” in the context of a population of molecules of identical molecular formula means a chiral center having a random stereochemical configuration. For example, in a population of molecules comprising a stereorandom chiral center, the number of molecules having the (S) configuration of the stereorandom chiral center may be but is not necessarily the same as the number of molecules having the (R) configuration of the stereorandom chiral center. The stereochemical configuration of a chiral center is considered random when it is the result of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, a stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage.

As used herein, “subject” means a human or non-human animal. In certain embodiments, the subject is a human.

As used herein, “sugar moiety” means an unmodified sugar moiety or a modified sugar moiety. As used herein, “unmodified sugar moiety” means a 2′-OH(H) β-D-ribosyl moiety, as found in RNA (an “unmodified RNA sugar moiety”), or a 2′-H(H) β-D-deoxyribosyl sugar moiety, as found in DNA (an “unmodified DNA sugar moiety”). Unmodified sugar moieties have one hydrogen at each of the 1′, 3′, and 4′ positions, an oxygen at the 3′ position, and two hydrogens at the 5′ position. As used herein, “modified sugar moiety” or “modified sugar” means a modified furanosyl sugar moiety or a sugar surrogate.

As used herein, “sugar surrogate” means a modified sugar moiety having other than a furanosyl moiety that can link a nucleobase to another group, such as an internucleoside linkage, conjugate group, or terminal group in an oligonucleotide. Modified nucleosides comprising sugar surrogates can be incorporated into one or more positions within an oligonucleotide and such oligonucleotides are capable of hybridizing to complementary oligomeric compounds or target nucleic acids.

As used herein, “symptom or hallmark” means any physical feature or test result that indicates the existence or extent of a disease or disorder. In certain embodiments, a symptom is apparent to a subject or to a medical professional examining or testing said subject. In certain embodiments, a hallmark is apparent upon invasive diagnostic testing, including, but not limited to, post-mortem tests. In certain embodiments, a hallmark is apparent on a brain MRI scan.

As used herein, “target nucleic acid” and “target RNA” mean a nucleic acid that an antisense compound is designed to affect. Target RNA means an RNA transcript and includes pre-mRNA and mature mRNA unless otherwise specified.

As used herein, “target region” means a portion of a target nucleic acid to which an oligomeric compound is designed to hybridize.

As used herein, “terminal group” means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide.

As used herein, “therapeutically effective amount” means an amount of a pharmaceutical agent that provides a therapeutic benefit to a subject. For example, a therapeutically effective amount improves a symptom or hallmark of a disease or disorder.

As used herein, “treating” means improving a subject's disease or disorder by administering an oligomeric agent or oligomeric compound described herein. In certain embodiments, treating a subject improves a symptom relative to the same symptom in the absence of the treatment. In certain embodiments, treatment reduces in the severity or frequency of a symptom, or delays the onset of a symptom, slows the progression of a symptom, or slows the severity or frequency of a symptom.

CERTAIN EMBODIMENTS

The present disclosure provides the following non-limiting numbered embodiments:

Embodiment 1. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to an equal length portion of an SCN2A nucleic acid, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.

Embodiment 2. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 16-2531, wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.

Embodiment 3. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or 18 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 2532-2539, wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.

Embodiment 4. The oligomeric compound of any of embodiments 1 to 3, wherein the modified oligonucleotide is at least 90% complementary to an equal length portion of SEQ ID NO: 2 and is not more than 50% complementary to an equal length portion of SEQ ID NO: 1.

Embodiment 5. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein

-   -   a) the nucleobase sequence of the modified oligonucleotide         comprises at least 8, at least 9, at least 10, at least 11, at         least 12, at least 13, at least 14, at least 15, at least 16, at         least 17, at least 18, at least 19, or at least 20 contiguous         nucleobases complementary to an equal length portion of         nucleobases 199863-199905, 227493-22755, 243124-243204,         247823-247921, 254142-254177, 168911-168945, 170026-170061,         183519-183562, 188630-188668, 199912-199962, 227419-227450, or         238173-238192 of SEQ ID NO: 2, provided that the modified         oligonucleotide does not comprise more than six LNA nucleosides;         or     -   b) the nucleobase sequence of the modified oligonucleotide         comprises at least 8, at least 9, at least 10, at least 11, at         least 12, at least 13, at least 14, at least 15, at least 16, at         least 17, at least 18, at least 19, or at least 20 contiguous         nucleobases complementary to an equal length portion of         nucleobases 243917-244073, 170174-170200, 176724-176751,         180772-180801, 183968-184016, 202877-202906, 224198-224217,         224199-224218, or 243918-243937 of SEQ ID NO: 2,     -   wherein the modified oligonucleotide comprises at least one         modification selected from a modified sugar moiety and a         modified internucleoside linkage.

Embodiment 6. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein

-   -   a) the nucleobase sequence of the modified oligonucleotide         comprises at least 8, at least 9, at least 10, at least 11, at         least 12, at least 13, at least 14, at least 15, at least 16, at         least 17, at least 18, at least 19, or at least 20 contiguous         nucleobases of a sequence selected from SEQ ID NOs: 336, 488,         2021, 2097, 2174, 2250, 2326, 2403, 2499, 2500, 2501, 2502,         2526; 181, 259, 643, 720, 796, 2504, 2505, 2506, 2507, 2508,         2509, 2510, 2511, 2512, 2513, 2514, 2521; 491, 567, 644, 721,         797, 2177, 2253, 2315, 2329, 2406, 2527; 29, 30, 107, 108, 185,         186, 263, 264, 341, 342, 419, 420, 1796, 1871, 1948, 2025, 2101,         2178, 2254, 2330, 2503, 2517, 2522; 1016, 1093, 1104, 1169,         1246, 1323, 1400, 1477, 1554, 1708, 1785, 1860, 1937, 2014,         1631, 2090, 2539; 18, 96, 485, 561, 638, 715, 791, 868, 2247,         2323, 2400; 174, 1328, 1405, 1482, 1559, 1636, 1713, 1790, 1865,         1942, 2019; 20, 98, 253, 332, 410, 1406, 1483, 1560, 1637, 1714,         1791, 1866, 1943; 21, 411, 1407, 1484, 1561, 1638, 1715; 24,         414, 871, 948, 1025, 1100; 25, 337, 415, 490, 566, 2099, 2176,         2252, 2328, 2405; and 182; provided that the modified         oligonucleotide does not comprise more than six LNA nucleosides;         or     -   b) wherein the nucleobase sequence of the modified         oligonucleotide comprises at least 8, at least 9, at least 10,         at least 11, at least 12, at least 13, at least 14, at least 15,         at least 16, at least 17, at least 18, at least 19, or at least         20 contiguous nucleobases of a sequence selected from SEQ ID         NOs: 1090, 1166, 2484, 2485, 2487, 2493, 2496, 2497, 2498, 2533,         2534, 2535, 2537; 302, 1513, 1667, 1744, 1819, 1896, 1973; 148,         226, 1364, 1441, 1518, 1595, 1672, 1749; 227, 1292, 1369, 1446,         1523, 1600, 1677, 1754, 1829; 228, 1679, 1756, 1831, 1908, 1985,         2061, 2138, 2214, 2290; 1226, 1303, 1380, 1457, 1534, 1611;         2079; 2523; and 2477     -   wherein the modified oligonucleotide comprises at least one         modification selected from a modified sugar moiety and a         modified internucleoside linkage.

Embodiment 7. The oligomeric compound of any of embodiments 1-6, comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of any of SEQ ID NOs: 2487, 2493, 2510, or 2514.

Embodiment 8. The oligomeric compound of any of embodiments 1-6, comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or 18 contiguous nucleobases of SEQ ID NO: 2534.

Embodiment 9. The oligomeric compound of any of embodiments 1-8, wherein the modified oligonucleotide has a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the nucleobase sequence of SEQ ID NO: 1 or SEQ ID NO: 2 when measured across the entire nucleobase sequence of the modified oligonucleotide.

Embodiment 10. The oligomeric compound of embodiment 9 wherein the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to

-   -   an intronic region of the nucleobase sequence of SEQ ID NO: 2;     -   an untranslated region of the nucleobase sequence of SEQ ID NO:         2; or     -   an intron/exon junction region of the nucleobase sequence of SEQ         ID NO: 2.

Embodiment 11. The oligomeric compound of any of embodiments 1-10, wherein the nucleobase sequence of the modified oligonucleotide is no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, or no more than 95% complementary to an exonic region of the nucleobase sequence of SEQ ID NO: 2.

Embodiment 12. The oligomeric compound of any of embodiments 1-11, wherein the modified oligonucleotide consists of 10 to 25, 10 to 30, 10 to 50, 12 to 20, 12 to 25, 12 to 30, 12 to 50, 13 to 20, 13 to 25, 13 to 30, 13 to 50, 14 to 20, 14 to 25, 14 to 30, 14 to 50, 15 to 20, 15 to 25, 15 to 30, 15 to 50, 16 to 18, 16 to 20, 16 to 25, 16 to 30, 16 to 50, 17 to 20, 17 to 25, 17 to 30, 17 to 50, 18 to 20, 18 to 25, 18 to 30, 18 to 50, 19 to 20, 19 to 25, 19 to 30, 19 to 50, 20 to 25, 20 to 30, 20 to 50, 21 to 25, 21 to 30, 21 to 50, 22 to 25, 22 to 30, 22 to 50, 23 to 25, 23 to 30, or 23 to 50 linked nucleosides.

Embodiment 13. The oligomeric compound of any of embodiments 1-11, wherein the modified oligonucleotide consists of 17-19 or 21-30 linked nucleosides.

Embodiment 14. The oligomeric compound of any of embodiments 1-13, wherein the modified oligonucleotide consists of 16, 17, 18, 19, or 20 linked nucleosides.

Embodiment 15. The oligomeric compound of embodiment 14, wherein the modified oligonucleotide consists of 20 linked nucleosides.

Embodiment 16. The oligomeric compound of embodiment 14, wherein the modified oligonucleotide consists of 18 linked nucleosides.

Embodiment 17. The oligomeric compound of any of embodiments 1-16, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified sugar moiety.

Embodiment 18. The oligomeric compound of embodiment 17, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety.

Embodiment 19. The oligomeric compound of embodiment 18, wherein the bicyclic sugar moiety comprises a 4′-2′ bridge, wherein the 4′-2′ bridge is selected from —CH₂—O—; and —CH(CH₃)—O—.

Embodiment 20. The oligomeric compound of any of embodiments 17-19, wherein the modified oligonucleotide does not comprise more than six bicyclic sugar moieties.

Embodiment 21. The oligomeric compound of embodiment 17, wherein the modified oligonucleotide does not comprise a bicyclic sugar moiety.

Embodiment 22. The oligomeric compound of any of embodiments 17-20, wherein the modified oligonucleotide does not comprise more than six LNA sugar moieties.

Embodiment 23. The oligomeric compound of any of embodiments 17-21, wherein the modified oligonucleotide does not comprise a LNA sugar moiety.

Embodiment 24. The oligomeric compound of any of embodiments 17-23, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic modified sugar moiety.

Embodiment 25. The oligomeric compound of embodiment 24, wherein the non-bicyclic modified sugar moiety is a 2′-MOE sugar moiety or a 2′-OMe sugar moiety.

Embodiment 26. The oligomeric compound of any of embodiments 17-25, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a sugar surrogate.

Embodiment 27. The oligomeric compound of embodiment 26, wherein the sugar surrogate is any of morpholino, modified morpholino, PNA, THP, and F-HNA.

Embodiment 28. The oligomeric compound of any of embodiments 1-27, wherein the modified oligonucleotide is a gapmer.

Embodiment 29. The oligomeric compound of any of embodiments 1-28, wherein the modified oligonucleotide comprises:

-   -   a 5′-region consisting of 1-6 linked 5′-region nucleosides;     -   a central region consisting of 6-10 linked central region         nucleosides; and     -   a 3′-region consisting of 1-6 linked 3′-region nucleosides;         wherein     -   each of the 5′-region nucleosides and each of the 3′-region         nucleosides comprises a modified sugar moiety and at least six         of the central region nucleosides comprise a 2′-β-D-deoxyribosyl         sugar moiety.

Embodiment 30. The oligomeric compound of any of embodiments 1-28, wherein the modified oligonucleotide comprises:

-   -   a 5′-region consisting of 1-6 linked 5′-region nucleosides;     -   a central region consisting of 6-10 linked central region         nucleosides; and     -   a 3′-region consisting of 1-6 linked 3′-region nucleosides;         wherein each of the 5′-region nucleosides and each of the         3′-region nucleosides comprises a modified sugar moiety and each         of the central region nucleosides comprises a         2′-β-D-deoxyribosyl sugar moiety.

Embodiment 31. The oligomeric compound of embodiment 29, wherein the modified oligonucleotide comprises: a 5′-region consisting of 5 linked 5′-region nucleosides;

-   -   a central region consisting of 10 linked central region         nucleosides; and     -   a 3′-region consisting of 5 linked 3′-region nucleosides;         wherein     -   each of the 5′-region nucleosides and each of the 3′-region         nucleosides comprises a 2′-MOE modified sugar moiety, and at         least six of the central region nucleosides comprise a         2′-β-D-deoxyribosyl sugar moiety.

Embodiment 32. The oligomeric compound of embodiment 30, wherein the modified oligonucleotide comprises:

-   -   a 5′-region consisting of 5 linked 5′-region nucleosides;     -   a central region consisting of 10 linked central region         nucleosides; and     -   a 3′-region consisting of 5 linked 3′-region nucleosides;         wherein     -   each of the 5′-region nucleosides and each of the 3′-region         nucleosides comprises a 2′-MOE modified sugar moiety, and each         of the central region nucleosides comprises a         2′-β-D-deoxyribosyl sugar moiety.

Embodiment 33. The oligomeric compound of embodiment 29, wherein the modified oligonucleotide comprises:

-   -   a 5′-region consisting of 6 linked 5′-region nucleosides;     -   a central region consisting of 10 linked central region         nucleosides; and     -   a 3′-region consisting of 4 linked 3′-region nucleosides;         wherein     -   each of the 5′-region nucleosides and each of the 3′-region         nucleosides comprises a 2′-MOE modified sugar moiety, and at         least six of the central region nucleosides comprise a         2′-β-D-deoxyribosyl sugar moiety.

Embodiment 34. The oligomeric compound of embodiment 30, wherein the modified oligonucleotide comprises:

-   -   a 5′-region consisting of 6 linked 5′-region nucleosides;     -   a central region consisting of 10 linked central region         nucleosides; and     -   a 3′-region consisting of 4 linked 3′-region nucleosides;         wherein     -   each of the 5′-region nucleosides and each of the 3′-region         nucleosides comprises a 2′-MOE modified sugar moiety, and each         of the central region nucleosides comprises a         2′-β-D-deoxyribosyl sugar moiety.

Embodiment 35. The oligomeric compound of embodiment 29, wherein the modified oligonucleotide comprises:

-   -   a 5′-region consisting of 4 linked 5′-region nucleosides;     -   a central region consisting of 10 linked central region         nucleosides; and     -   a 3′-region consisting of 6 linked 3′-region nucleosides;         wherein     -   each of the 5′-region nucleosides and each of the 3′-region         nucleosides comprises a 2′-MOE modified sugar moiety, and at         least six of the central region nucleosides comprise a         2′-β-D-deoxyribosyl sugar moiety.

Embodiment 36. The oligomeric compound of embodiment 30, wherein the modified oligonucleotide comprises:

-   -   a 5′-region consisting of 4 linked 5′-region nucleosides;     -   a central region consisting of 10 linked central region         nucleosides; and     -   a 3′-region consisting of 6 linked 3′-region nucleosides;         wherein     -   each of the 5′-region nucleosides and each of the 3′-region         nucleosides comprises a 2′-MOE modified sugar moiety, and each         of the central region nucleosides comprises a         2′-β-D-deoxyribosyl sugar moiety.

Embodiment 37. The oligomeric compound of embodiment 29, wherein the modified oligonucleotide comprises:

-   -   a 5′-region consisting of 4 linked 5′-region nucleosides;     -   a central region consisting of 8 linked central region         nucleosides; and     -   a 3′-region consisting of 6 linked 3′-region nucleosides;         wherein     -   each of the 5′-region nucleosides and each of the 3′-region         nucleosides comprises a 2′-MOE modified sugar moiety, and at         least six of the central region nucleosides comprise a         2′-β-D-deoxyribosyl sugar moiety.

Embodiment 38. The oligomeric compound of embodiment 30, wherein the modified oligonucleotide comprises:

-   -   a 5′-region consisting of 4 linked 5′-region nucleosides;     -   a central region consisting of 8 linked central region         nucleosides; and     -   a 3′-region consisting of 6 linked 3′-region nucleosides;         wherein     -   each of the 5′-region nucleosides and each of the 3′-region         nucleosides comprises a 2′-MOE modified sugar moiety, and each         of the central region nucleosides comprises a         2′-β-D-deoxyribosyl sugar moiety.

Embodiment 39. The oligomeric compound of embodiment 29, wherein the modified oligonucleotide comprises:

-   -   a 5′-region consisting of 6 linked 5′-region nucleosides;     -   a central region consisting of 8 linked central region         nucleosides; and     -   a 3′-region consisting of 4 linked 3′-region nucleosides;         wherein     -   each of the 5′-region nucleosides and each of the 3′-region         nucleosides comprises a 2′-MOE modified sugar moiety, and at         least six of the central region nucleosides comprise a         2′-β-D-deoxyribosyl sugar moiety.

Embodiment 40. The oligomeric compound of embodiment 30, wherein the modified oligonucleotide comprises:

-   -   a 5′-region consisting of 6 linked 5′-region nucleosides;     -   a central region consisting of 8 linked central region         nucleosides; and     -   a 3′-region consisting of 4 linked 3′-region nucleosides;         wherein     -   each of the 5′-region nucleosides and each of the 3′-region         nucleosides comprises a 2′-MOE modified sugar moiety, and each         of the central region nucleosides comprises a         2′-β-D-deoxyribosyl sugar moiety.

Embodiment 41. The oligomeric compound of embodiment 29, wherein the modified oligonucleotide comprises:

-   -   a 5′-region consisting of 5 linked 5′-region nucleosides;     -   a central region consisting of 8 linked central region         nucleosides; and     -   a 3′-region consisting of 5 linked 3′-region nucleosides;         wherein     -   each of the 5′-region nucleosides and each of the 3′-region         nucleosides comprises a 2′-MOE modified sugar moiety, and at         least six of the central region nucleosides comprise a         2′-β-D-deoxyribosyl sugar moiety.

Embodiment 42. The oligomeric compound of embodiment 30, wherein the modified oligonucleotide comprises:

-   -   a 5′-region consisting of 5 linked 5′-region nucleosides;     -   a central region consisting of 8 linked central region         nucleosides; and     -   a 3′-region consisting of 5 linked 3′-region nucleosides;         wherein     -   each of the 5′-region nucleosides and each of the 3′-region         nucleosides comprises a 2′-MOE modified sugar moiety, and each         of the central region nucleosides comprises a         2′-β-D-deoxyribosyl sugar moiety.

Embodiment 43. The oligomeric compound of embodiment 29 or embodiment 30, wherein the 5′-region or the 3′-region comprises at least one bicyclic nucleoside.

Embodiment 44. The oligomeric compound of embodiment 29 or embodiment 30, wherein the 5′-region or the 3′-region comprises at least one nucleoside that is not a bicyclic nucleoside.

Embodiment 45. The oligomeric compound of embodiment 29 or embodiment 30, wherein the 5′-region or the 3′-region comprises at least one nucleoside that is not a LNA nucleoside.

Embodiment 46. The oligomeric compound of any of embodiments 1-45, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

Embodiment 47. The oligomeric compound of embodiment 46, wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

Embodiment 48. The oligomeric compound of embodiment 46 or embodiment 47, wherein each internucleoside linkage is a modified internucleoside linkage.

Embodiment 49. The oligomeric compound of embodiment 48, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

Embodiment 50. The oligomeric compound of any of embodiments 46-47, wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphodiester internucleoside linkage.

Embodiment 51. The oligomeric compound of any of embodiments 1-46, wherein each internucleoside linkage of the modified oligonucleotide is independently selected from a phosphodiester or a phosphorothioate internucleoside linkage.

Embodiment 52. The oligomeric compound of any of embodiments 1-47 or 50-51, wherein at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 internucleoside linkages of the modified oligonucleotide are phosphorothioate internucleoside linkages.

Embodiment 53. The oligomeric compound of embodiment 46, wherein the internucleoside linkage motif of the modified oligonucleotide is selected from soooossssssssssooss, sooooossssssssssoss, sooossssssssssoooss, soosssssssssoooss, soooosssssssssoss, and sooosssssssssooss, wherein s=a phosphorothioate internucleoside linkage and o=a phosphodiester internucleoside linkage.

Embodiment 54. The oligomeric compound of any of embodiments 1-53, wherein the modified oligonucleotide comprises at least one modified nucleobase.

Embodiment 55. The oligomeric compound of embodiment 54, wherein the modified nucleobase is a 5-methyl cytosine.

Embodiment 56. The oligomeric compound of any of embodiments 1-55, wherein the oligomeric compound is capable of reducing the amount of SCN2A RNA in vitro by at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% when administered according to a standard in vitro assay.

Embodiment 57. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: G_(es) ^(m)C_(eo)A_(eo)T_(eo)A_(eo)A_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(eo) ^(m)C_(eo)A_(es)A_(es)A_(e) (SEQ ID NO: 2493), wherein:

-   -   A=an adenine nucleobase,     -   mC=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE sugar moiety,     -   d=a 2′-β-D-deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internmucleoside linkage.

Embodiment 58. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:

(SEQ ID NO: 2514) ^(m)C_(es)A_(eo) ^(m)C_(eo)G_(eo)A_(eo) ^(m)C_(eo)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds) T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(eo) ^(m)C_(es)A_(es) ^(m)C_(e), wherein:

-   -   A=an adenine nucleobase,     -   ^(m)C=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE sugar moiety,     -   d=a 2′-β-D-deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

Embodiment 59. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:

(SEQ ID NO: 2510) ^(m)C_(es) ^(m)C_(eo)A_(eo) ^(m)C_(eo)G_(eo)A_(eo) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds) T_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(eo)A_(es) ^(m)C_(es)A_(e), wherein:

-   -   A=an adenine nucleobase,     -   ^(m)C=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE sugar moiety,     -   d=a 2′-β-D-deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

Embodiment 60. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:

(SEQ ID NO: 2487) T_(es) ^(m)C_(eo)T_(eo)G_(eo) ^(m)C_(eo)A_(eo)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(eo)T_(es)A_(es) ^(m)C_(e), wherein:

-   -   A=an adenine nucleobase,     -   mC=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE sugar moiety,     -   d=a 2′-β-D-deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

Embodiment 61. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:

(SEQ ID NO: 2493) G_(es) ^(m)C_(eo)A_(eo)T_(eo)A_(eo)A_(eo)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds) A_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(eo)A_(es)A_(es)A_(e), wherein:

-   -   A=an adenine nucleobase,     -   ^(m)C=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE sugar moiety,     -   d=a 2′-β-D-deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

Embodiment 62. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:

(SEQ ID NO: 2534) GT^(m)C_(es)T_(eo)G_(eo) ^(m)C_(eo)A_(es)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(eo)T_(eo)A_(es)T_(es)A_(e), wherein:

-   -   A=an adenine nucleobase,     -   ^(m)C=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE sugar moiety,     -   d=a 2′-β-D-deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

Embodiment 63. The oligomeric compound of any of embodiments 1-62 wherein the oligomeric compound is a singled-stranded oligomeric compound.

Embodiment 64. The oligomeric compound of any of embodiments 1-63, wherein the modified oligonucleotide of the oligomeric compound is a salt, and wherein the salt is a sodium salt or a potassium salt.

Embodiment 65. The oligomeric compound of any of embodiments 1-64, consisting of the modified oligonucleotide.

Embodiment 66. The oligomeric compound of any of embodiments 1-62, wherein the modified oligonucleotide is an RNAi compound.

Embodiment 67. The oligomeric compound of any of embodiments 1-66, further comprising a conjugate group.

Embodiment 68. The oligomeric compound of embodiment 67, wherein the conjugate group comprises a conjugate moiety and a conjugate linker.

Embodiment 69. The oligomeric compound of embodiment 68, wherein the conjugate group comprises a GalNAc cluster comprising 1-3 GalNAc ligands.

Embodiment 70. The oligomeric compound of embodiment 68, wherein the conjugate linker consists of a single bond.

Embodiment 71. The oligomeric compound of embodiment 68, wherein the conjugate linker is cleavable.

Embodiment 72. The oligomeric compound of embodiment 68, wherein the conjugate linker comprises 1-3 linker-nucleosides.

Embodiment 73. The oligomeric compound of any of embodiments 67-72, wherein the conjugate group is attached to the modified oligonucleotide at the 5′-end of the modified oligonucleotide.

Embodiment 74. The oligomeric compound of any of embodiments 67-72, wherein the conjugate group is attached to the modified oligonucleotide at the 3′-end of the modified oligonucleotide.

Embodiment 75. The oligomeric compound of any of embodiments 1-74 further comprising a terminal group.

Embodiment 76. The oligomeric compound of any of embodiments 1-71 or 73-75, wherein the oligomeric compound does not comprise linker-nucleosides.

Embodiment 77. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.

Embodiment 78. The modified oligonucleotide of embodiment 77, which is the sodium salt or the potassium salt.

Embodiment 79. A modified oligonucleotide according to the following chemical structure:

Embodiment 80. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.

Embodiment 81. The modified oligonucleotide of embodiment 80, which is the sodium salt or the potassium salt.

Embodiment 82. A modified oligonucleotide according to the following chemical structure:

Embodiment 83. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.

Embodiment 84. The modified oligonucleotide of embodiment 83, which is the sodium salt or the potassium salt.

Embodiment 85. A modified oligonucleotide according to the following chemical structure:

Embodiment 86. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.

Embodiment 87. The modified oligonucleotide of embodiment 86, which is the sodium salt or the potassium salt.

Embodiment 88. A modified oligonucleotide according to the following chemical structure:

Embodiment 89. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.

Embodiment 90. The modified oligonucleotide of embodiment 89, which is the sodium salt or the potassium salt.

Embodiment 91. A modified oligonucleotide according to the following chemical structure:

Embodiment 92. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.

Embodiment 93. The modified oligonucleotide of embodiment 92, which is the sodium salt or the potassium salt.

Embodiment 94. A modified oligonucleotide according to the following chemical structure:

Embodiment 95. A chirally enriched population of oligomeric compounds of any of embodiments 1-76 or modified oligonucleotides of any of embodiments 77-94, wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration.

Embodiment 96. The chirally enriched population of embodiment 95, wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Sp) configuration.

Embodiment 97. The chirally enriched population of embodiment 95, wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Rp) configuration.

Embodiment 98. The chirally enriched population of embodiment 95, wherein the population is enriched for modified oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage.

Embodiment 99. The chirally enriched population of embodiment 98, wherein the population is enriched for modified oligonucleotides having the (Sp) configuration at each phosphorothioate internucleoside linkage or for modified oligonucleotides having the (Rp) configuration at each phosphorothioate internucleoside linkage.

Embodiment 100. The chirally enriched population of embodiment 98, wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at one particular phosphorothioate internucleoside linkage and the (Sp) configuration at each of the remaining phosphorothioate internucleoside linkages.

Embodiment 101. The chirally enriched population of embodiment 98, wherein the population is enriched for modified oligonucleotides having at least 3 contiguous phosphorothioate internucleoside linkages in the Sp, Sp, and Rp configurations, in the 5′ to 3′ direction.

Embodiment 102. A population of oligomeric compounds of any of embodiments 1-76 or modified oligonucleotides of any of embodiments 77-94, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

Embodiment 103. An oligomeric duplex, comprising a first oligomeric compound and a second oligomeric compound comprising a second modified oligonucleotide, wherein the first oligomeric compound is an oligomeric compound of any of embodiments 1-76.

Embodiment 104. The oligomeric duplex of embodiment 103, wherein the second oligomeric compound comprises a second modified oligonucleotide consisting of 8 to 80 linked nucleosides, and wherein the nucleobase sequence of the second modified oligonucleotide comprises a complementary region of at least 8 nucleobases that is at least 90% complementary to an equal length portion of the first modified oligonucleotide.

Embodiment 105. An antisense agent comprising an antisense compound, wherein the antisense compound is an oligomeric compound of any of embodiments 1-76 or a modified oligonucleotide of any of embodiments 77-94.

Embodiment 106. The antisense agent of embodiment 103, wherein the antisense agent is an oligomeric duplex of embodiment 103 or embodiment 104.

Embodiment 107. The antisense agent of embodiment 105 or embodiment 106, wherein the antisense agent is:

-   -   i. an RNase H agent capable of reducing the amount of SCN2A         nucleic acid through the activation of RNase H; or     -   ii. an RNAi agent capable of reducing the amount of SCN2A         nucleic acid through the activation of RISC/Ago2.

Embodiment 108. A pharmaceutical composition comprising an oligomeric compound of any of embodiments 1-76, a modified oligonucleotide of any of embodiments 77-94, a population of any of embodiments 95-102, an oligomeric duplex of embodiment 103 or embodiment 104, or an antisense agent of any of embodiments 105-107, and a pharmaceutically acceptable diluent or carrier.

Embodiment 109. The pharmaceutical composition of embodiment 108, comprising a pharmaceutically acceptable diluent and wherein the pharmaceutically acceptable diluent is artificial CSF (aCSF) or phosphate-buffered saline (PBS).

Embodiment 110. The pharmaceutical composition of embodiment 109, wherein the pharmaceutical composition consists essentially of the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, or the antisense agent, and aCSF.

Embodiment 111. The pharmaceutical composition of embodiment 109, wherein the pharmaceutical composition consists essentially of the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, or the antisense agent, and PBS.

Embodiment 112. A pharmaceutical composition comprising a modified oligonucleotide of any of embodiments 77-94 and a pharmaceutically acceptable diluent.

Embodiment 113. The pharmaceutical composition of embodiment 112, wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid (aCSF) or phosphate-buffered saline (PBS).

Embodiment 114. The pharmaceutical composition of embodiment 113, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and aCSF.

Embodiment 115. The pharmaceutical composition of embodiment 113, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.

Embodiment 116. A method comprising administering to a subject an oligomeric compound of any of embodiments 1-76, a modified oligonucleotide of any of embodiments 77-94, a population of any of embodiments 95-102, an oligomeric duplex of embodiment 103 or embodiment 104, an antisense agent of any of embodiments 105-107, or a pharmaceutical composition of any of embodiments 108-115.

Embodiment 117. A method of treating a disease or disorder associated with a voltage-gated sodium channel protein, comprising administering to a subject having or at risk for developing the disease or disorder associated with a voltage-gated sodium channel protein a therapeutically effective amount of an oligomeric compound of any of embodiments 1-76, a modified oligonucleotide of any of embodiments 77-94, a population of any of embodiments 95-102, an oligomeric duplex of embodiment 103 or embodiment 104, an antisense agent of any of embodiments 105-107, or a pharmaceutical composition of any of embodiments 108-115, thereby treating the disease or disorder associated with a voltage-gated sodium channel protein.

Embodiment 118. A method of reducing the amount of SCN2A protein in the CSF of a subject having or at risk for developing a disease or disorder associated with a voltage-gated sodium channel protein a therapeutically effective amount of an oligomeric compound of any of embodiments 1-76, a modified oligonucleotide of any of embodiments 77-94, a population of any of embodiments 95-102, an oligomeric duplex of embodiment 103 or embodiment 104, an antisense agent of any of embodiments 105-107, or a pharmaceutical composition of any of embodiments 108-115, thereby reducing the amount of SCN2A protein in the CSF.

Embodiment 119. The method of embodiment 117 or embodiment 118, wherein the disease or disorder is a neurodevelopmental disease.

Embodiment 120. The method of embodiment 117 or embodiment 118, wherein the disease or disorder is associated with SCN1A or SCN2A.

Embodiment 121. A method of treating a disease or disorder associated with SCN2A, comprising administering to an subject having or at risk for developing a disease or disorder associated with SCN2A a therapeutically effective amount of an oligomeric compound of any of embodiments 1-76, a modified oligonucleotide of any of embodiments 77-94, a population of any of embodiments 95-102, an oligomeric duplex of embodiment 103 or embodiment 104, an antisense agent of any of embodiments 105-107, or a pharmaceutical composition of any of embodiments 108-115, thereby treating the disease or disorder associated with SCN2A.

Embodiment 122. The method of embodiment 121, wherein the disease or disorder associated with SCN2A is a Developmental and Epileptic Encephalopathy, an intellectual disability, or an autism spectrum disorder.

Embodiment 123. The method of embodiment 122, wherein the Developmental and Epileptic Encephalopathy is any of Early Seizure Onset Epileptic Encephalopathy (EE), Late Seizure Onset Epileptic Encephalopathy, or Benign Familial Neonatal-Infantile Seizures.

Embodiment 124. The method of embodiment 121, wherein the disease or disorder associated with SCN2A is any of Ohtahara Syndrome, epilepsy with migrating focal seizures of infancy, West Syndrome, Lennon-Gastaut Syndrome; Dravet Syndrome; Idiopathic/Generic Generalized Epilepsies, Temporal Lobe Epilepsy, Myoclonic Astatic Epilepsy, Migrating Partial Epilepsy of Infancy, or familial hemiplegic migraines.

Embodiment 125. The method of any of embodiments 118-120, wherein the disease or disorder is associated with SCN1A.

Embodiment 126. The method of embodiment 125, wherein the disease or disorder associated with SCN1A is a Developmental and Epileptic Encephalopathy.

Embodiment 127. The method of embodiment 125 or embodiment 126, wherein the Developmental and Epileptic Encephalopathy is Dravet Syndrome.

Embodiment 128. The method of embodiment 126 or embodiment 127, wherein the Developmental and Epileptic Encephalopathy is any of Ohtahara Syndrome, epilepsy with migrating focal seizures of infancy, West Syndrome, Lennon-Gastaut Syndrome; Dravet Syndrome; Idiopathic/Generic Generalized Epilepsies, Temporal Lobe Epilepsy, Myoclonic Astatic Epilepsy, Migrating Partial Epilepsy of Infancy, or familial hemiplegic migraines.

Embodiment 129. The method of any of embodiments 117-128, wherein at least one symptom or hallmark of the disease or disorder is ameliorated.

Embodiment 130. The method of embodiment 129, wherein the symptom or hallmark is seizures.

Embodiment 131. The method of any of embodiment 130, wherein the seizures are any of focal, clonic, tonic, generalized tonic and clonic, convulsive, myoclonic, absence, or obtundation status.

Embodiment 132. The method of embodiment 130, wherein the seizures are any of focal, clonic, tonic, or generalized tonic.

Embodiment 133. The method of embodiment 129, wherein the symptom or hallmark is any of seizures, hypotonia, sensory integration disorders, motor dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, visual dysfunctions, delayed language and speech, gastrointestinal disorders, neurodevelopmental delays, or sudden unexpected death in epilepsy.

Embodiment 134. The method of embodiment 129, wherein the symptom or hallmark is any of motor development delays, delayed social and language milestones, repetitive actions, uncoordinated oral movements, gastrointestinal disoders, sleep problems, or seizures.

Embodiment 135. The method of any of embodiments 130-134, wherein the seizures are frequent or prolonged.

Embodiment 136. The method of any of embodiments 116-135 wherein administering the modified oligonucleotide reduces seizures, sensory integration disorders, motor dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, visual dysfunctions, delayed language and speech, gastrointestinal disorders, neurodevelopmental delays, motor development delays, delayed social milestones, repetitive actions, uncoordinated oral movements, or sleep problems, or delays death in the subject.

Embodiment 137. The method of any of embodiments 116-136, wherein the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, the antisense agent, or the pharmaceutical composition is administered to the central nervous system or systemically.

Embodiment 138. The method of any of embodiments 116-136, wherein the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, the antisense agent, or the pharmaceutical composition is administered to the central nervous system and systemically.

Embodiment 139. The method of any of embodiments 111-131, wherein the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, the antisense agent, or the pharmaceutical composition is administered by any of intrathecally, systemically, subcutaneously, or intramuscularly.

Embodiment 140. The method of any of embodiments 116-139, wherein the subject is human.

Embodiment 141. A method of reducing the amount of SCN2A RNA in a cell comprising contacting the cell with an oligomeric compound of any of embodiments 1-76, a modified oligonucleotide of any of embodiments 77-94, a population of any of embodiments 95-102, an oligomeric duplex of embodiment 103 or embodiment 104, an antisense agent of any of embodiments 105-107, or a pharmaceutical composition of any of embodiments 108-115, thereby reducing the amount of SCN2A RNA in the cell.

Embodiment 142. A method of reducing the amount of SCN2A protein in a cell comprising contacting the cell with an oligomeric compound of any of embodiments 1-76, a modified oligonucleotide of any of embodiments 77-94, a population of any of embodiments 95-102, an oligomeric duplex of embodiment 103 or embodiment 104, an antisense agent of any of embodiments 105-107, or a pharmaceutical composition of any of embodiments 108-115, thereby reducing the amount of SCN2A protein in the cell.

Embodiment 143. The method of embodiment 141 or embodiment 142, wherein the cell is a cortical cell, a hippocampal cell, or a spinal cord cell.

Embodiment 144. The method of any of embodiments 141-143, wherein the cell is in an animal.

Embodiment 145. The method of any of embodiments 141-144, wherein the cell is a human cell.

Embodiment 146. Use of an oligomeric compound of any of embodiments 1-76, a modified oligonucleotide of any of embodiments 77-94, a population of any of embodiments 95-102, an oligomeric duplex of embodiment 103 or embodiment 104, an antisense agent of any of embodiments 105-107, or a pharmaceutical composition of any of embodiments 108-115 for reducing SCN2A expression in a cell.

Embodiment 147. The use of embodiment 146, wherein the level of SCN2A RNA in the cell is reduced.

Embodiment 148. The use of embodiment 146 or embodiment 147, wherein the level of SCN2A protein in the cell is reduced.

Embodiment 149. The use of any of embodiments 146-148, wherein the cell is a corical cell, a hippocampal cell, or a spinal cord cell.

I. Certain Oligonucleotides

In certain embodiments, provided herein are oligomeric compounds comprising oligonucleotides, which consist of linked nucleosides. Oligonucleotides may be unmodified oligonucleotides (RNA or DNA) or may be modified oligonucleotides. Modified oligonucleotides comprise at least one modification relative to unmodified RNA or DNA. That is, modified oligonucleotides comprise at least one modified nucleoside (comprising a modified sugar moiety and/or a modified nucleobase) and/or at least one modified internucleoside linkage.

A. Certain Modified Nucleosides

Modified nucleosides comprise a modified sugar moiety or a modified nucleobase or both a modified sugar moiety and a modified nucleobase.

1. Certain Sugar Moieties

In certain embodiments, modified sugar moieties are non-bicyclic modified sugar moieties. In certain embodiments, modified sugar moieties are bicyclic or tricyclic sugar moieties. In certain embodiments, modified sugar moieties are sugar surrogates. Such sugar surrogates may comprise one or more substitutions corresponding to those of other types of modified sugar moieties.

In certain embodiments, modified sugar moieties are non-bicyclic modified sugar moieties comprising a furanosyl ring with one or more substituent groups none of which bridges two atoms of the furanosyl ring to form a bicyclic structure. Such non bridging substituents may be at any position of the furanosyl, including but not limited to substituents at the 2′, 4′, and/or 5′ positions. In certain embodiments one or more non-bridging substituent of non-bicyclic modified sugar moieties is branched. Examples of 2′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 2′-F, 2′-OCH₃ (“OMe” or “O-methyl”), and 2′-O(CH₂)₂OCH₃ (“MOE” or “O-methoxyethyl”). In certain embodiments, 2′-substituent groups are selected from among: halo, allyl, amino, azido, SH, CN, OCN, CF₃, OCF₃, O—C₁-C₁₀ alkoxy, O—C₁-C₁₀ substituted alkoxy, O—C₁-C₁₀ alkyl, O—C₁-C₁₀ substituted alkyl, S-alkyl, N(R_(m))-alkyl, O-alkenyl, S-alkenyl, N(R_(m))-alkenyl, O-alkynyl, S-alkynyl, N(R_(m))-alkynyl, O-alkylenyl-O-alkyl, alkynyl, alkaryl, aralkyl, O-alkaryl, O-aralkyl, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_(m))(R_(n)) or OCH₂C(═O)—N(R_(m))(R_(n)), where each R_(m) and R_(n) is, independently, H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀ alkyl, and the 2′-substituent groups described in Cook et al., U.S. Pat. No. 6,531,584; Cook et al., U.S. Pat. No. 5,859,221; and Cook et al., U.S. Pat. No. 6,005,087. Certain embodiments of these 2′-substituent groups can be further substituted with one or more substituent groups independently selected from among: hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO₂), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl and alkynyl. Examples of 4′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015/106128. Examples of 5′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 5′-methyl (R or S), 5′-vinyl, and 5′-methoxy. In certain embodiments, non-bicyclic modified sugar moieties comprise more than one non-bridging sugar substituent, for example, 2′-F-5′-methyl sugar moieties and the modified sugar moieties and modified nucleosides described in Migawa et al., WO 2008/101157 and Rajeev et al., US2013/0203836.

In certain embodiments, a 2′-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2′-substituent group selected from: F, NH₂, N₃, OCF₃, OCH₃, O(CH₂)₃NH₂, CH₂CH═CH₂, OCH₂CH═CH₂, OCH₂CH₂OCH₃, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_(m))(R_(n)), O(CH₂)₂O(CH₂)₂N(CH₃)₂, and N-substituted acetamide (OCH₂C(═O)—N(R_(m))(R_(n))), where each R_(m) and R_(n) is, independently, H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀ alkyl.

In certain embodiments, a 2′-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2′-substituent group selected from: F, OCF₃, OCH₃, OCH₂CH₂OCH₃, O(CH₂)₂SCH₃, O(CH₂)₂ON(CH₃)₂, O(CH₂)₂O(CH₂)₂N(CH₃)₂, and OCH₂C(═O)—N(H)CH₃ (“NMA”).

In certain embodiments, a 2′-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2′-substituent group selected from: F, OCH₃, and OCH₂CH₂OCH₃.

In certain embodiments, modified furanosyl sugar moieties and nucleosides incorporating such modified furanosyl sugar moieties are further defined by isomeric configuration. For example, a 2′-deoxyfuranosyl sugar moiety may be in seven isomeric configurations other than the naturally occurring β-D-deoxyribosyl configuration. Such modified sugar moieties are described in, e.g., WO 2019/157531, incorporated by reference herein. A 2′-modified sugar moiety has an additional stereocenter at the 2′-position relative to a 2′-deoxyfuranosyl sugar moiety; therefore, such sugar moieties have a total of sixteen possible isomeric configurations. 2′-modified sugar moieties described herein are in the β-D-ribosyl isomeric configuration unless otherwise specified.

Certain modified sugar moieties comprise a substituent that bridges two atoms of the furanosyl ring to form a second ring, resulting in a bicyclic sugar moiety. Nucleosides comprising such bicyclic sugar moieties have been referred to as bicyclic nucleosides (BNAs), locked nucleosides, or conformationally restricted nucleotides (CRN). Certain such compounds are described in US Patent Publication No. 2013/0190383; and PCT publication WO 2013/036868. In certain such embodiments, the bicyclic sugar moiety comprises a bridge between the 4′ and the 2′ furanose ring atoms. In certain such embodiments, the furanose ring is a ribose ring. Examples of such 4′ to 2′ bridging sugar substituents include but are not limited to: 4′-CH₂-2′, 4′-(CH₂)₂-2′, 4′-(CH₂)₃-2′, 4′-CH₂—O-2′ (“LNA”), 4′-CH₂—S-2′, 4′-(CH₂)₂—O-2′ (“ENA”), 4′-CH(CH₃)—O-2′ (referred to as “constrained ethyl” or “cEt” when in the S configuration), 4′-CH₂—O—CH₂-2′, 4′-CH₂—N(R)-2′, 4′-CH(CH₂OCH₃)—O-2′ (“constrained MOE” or “cMOE”) and analogs thereof (see, e.g., Seth et al., U.S. Pat. No. 7,399,845, Bhat et al., U.S. Pat. No. 7,569,686, Swayze et al., U.S. Pat. No. 7,741,457, and Swayze et al., U.S. Pat. No. 8,022,193), 4′-C(CH₃)(CH₃)—O-2′ and analogs thereof (see, e.g., Seth et al., U.S. Pat. No. 8,278,283), 4′-CH₂—N(OCH₃)-2′ and analogs thereof (see, e.g., Prakash et al., U.S. Pat. No. 8,278,425), 4′-CH₂—O—N(CH₃)-2′ (see, e.g., Allerson et al., U.S. Pat. No. 7,696,345 and Allerson et al., U.S. Pat. No. 8,124,745), 4′-CH₂—C(H)(CH₃)-2′ (see, e.g., Zhou, et al., J Org. Chem., 2009, 74, 118-134), 4′-CH₂—C(═CH₂)-2′ and analogs thereof (see e.g., Seth et al., U.S. Pat. No. 8,278,426), 4′-C(R_(a)R_(b))—N(R)—O-2′, 4′-C(R_(a)R_(b))—O—N(R)-2′, 4′-CH₂—O—N(R)-2′, and 4′-CH₂—N(R)—O-2′, wherein each R, R_(a), and R_(b) is, independently, H, a protecting group, or C₁-C₁₂ alkyl (see, e.g. Imanishi et al., U.S. Pat. No. 7,427,672). In certain embodiments, such 4′ to 2′ bridges independently comprise from 1 to 4 linked groups independently selected from: —[C(R_(a))(R_(b))]_(n)—, —[C(R_(a))(R_(b))]_(n)O—, —C(R_(a))═C(R_(b))—, —C(R_(a))═N—, —C(═NR_(a))—, —C(═O)—, —C(═S)—, —O—, —Si(R_(a))₂—, —S(═O)_(x)—, and —N(R_(a))—;

-   -   wherein:     -   x is 0, 1, or 2;     -   n is 1, 2, 3, or 4;     -   each R_(a) and R_(b) is, independently, H, a protecting group,         hydroxyl, C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂         alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted         C₂-C₁₂ alkynyl, C₅-C₂₀ aryl, substituted C₅-C₂₀ aryl,         heterocycle radical, substituted heterocycle radical,         heteroaryl, substituted heteroaryl, C₅-C₇ alicyclic radical,         substituted C₅-C₇ alicyclic radical, halogen, OJ₁, NJ₁J₂, SJ₁,         N₃, COOJ₁, acyl (C(═O)—H), substituted acyl, CN, sulfonyl         (S(═O)₂-J₁), or sulfoxyl (S(═O)-J₁); and     -   each J₁ and J₂ is, independently, H, C₁-C₁₂ alkyl, substituted         C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂         alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl, substituted         C₅-C₂₀ aryl, acyl (C(═O)—H), substituted acyl, a heterocycle         radical, a substituted heterocycle radical, C₁-C₁₂ aminoalkyl,         substituted C₁-C₁₂ aminoalkyl, or a protecting group.

Additional bicyclic sugar moieties are known in the art, see, for example: Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443, Albaek et al., J. Org. Chem., 2006, 71, 7731-7740, Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Wahlestedt et al., Proc. Natl. Acad. Sci. U.S.A, 2000, 97, 5633-5638; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Srivastava et al., J. Am. Chem. Soc., 2007, 129, 8362-8379; Elayadi et al., Curr. Opinion Invens. Drugs, 2001, 2, 558-561; Braasch et al., Chem. Biol., 2001, 8, 1-7; Orum et al., Curr. Opinion Mol. Ther., 2001, 3, 239-243; Wengel et al., U.S. Pat. No. 7,053,207, Imanishi et al., U.S. Pat. No. 6,268,490, Imanishi et al. U.S. Pat. No. 6,770,748, Imanishi et al., U.S. Pat. No. RE44,779; Wengel et al., U.S. Pat. No. 6,794,499, Wengel et al., U.S. Pat. No. 6,670,461; Wengel et al., U.S. Pat. No. 7,034,133, Wengel et al., U.S. Pat. No. 8,080,644; Wengel et al., U.S. Pat. No. 8,034,909; Wengel et al., U.S. Pat. No. 8,153,365; Wengel et al., U.S. Pat. No. 7,572,582; and Ramasamy et al., U.S. Pat. No. 6,525,191, Torsten et al., WO 2004/106356, Wengel et al., WO 1999/014226; Seth et al., WO 2007/134181; Seth et al., U.S. Pat. No. 7,547,684; Seth et al., U.S. Pat. No. 7,666,854; Seth et al., U.S. Pat. No. 8,088,746; Seth et al., U.S. Pat. No. 7,750,131; Seth et al., U.S. Pat. No. 8,030,467; Seth et al., U.S. Pat. No. 8,268,980; Seth et al., U.S. Pat. No. 8,546,556; Seth et al., U.S. Pat. No. 8,530,640; Migawa et al., U.S. Pat. No. 9,012,421; Seth et al., U.S. Pat. No. 8,501,805; Allerson et al., US2008/0039618; and Migawa et al., US2015/0191727.

In certain embodiments, bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by isomeric configuration. For example, an LNA nucleoside (described herein) may be in the α-L configuration or in the β-D configuration.

-   -   α-L-methyleneoxy (4′-CH₂—O-2′) or α-L-LNA bicyclic nucleosides         have been incorporated into oligonucleotides that showed         antisense activity (Frieden et al., Nucleic Acids Research,         2003, 21, 6365-6372). Herein, general descriptions of bicyclic         nucleosides include both isomeric configurations. When the         positions of specific bicyclic nucleosides (e.g., LNA or cEt)         are identified in exemplified embodiments herein, they are in         the β-D configuration, unless otherwise specified.

In certain embodiments, modified sugar moieties comprise one or more non-bridging sugar substituent and one or more bridging sugar substituent (e.g., 5′-substituted and 4′-2′ bridged sugars).

In certain embodiments, modified sugar moieties are sugar surrogates. In certain such embodiments, the oxygen atom of the sugar moiety is replaced, e.g., with a sulfur, carbon or nitrogen atom. In certain such embodiments, such modified sugar moieties also comprise bridging and/or non-bridging substituents as described herein. For example, certain sugar surrogates comprise a 4′-sulfur atom and a substitution at the 2-position (see, e.g., Bhat et al., U.S. Pat. No. 7,875,733 and Bhat et al., U.S. Pat. No. 7,939,677) and/or the 5′ position.

In certain embodiments, sugar surrogates comprise rings having other than 5 atoms. For example, in certain embodiments, a sugar surrogate comprises a six-membered tetrahydropyran (“THP”). Such tetrahydropyrans may be further modified or substituted. Nucleosides comprising such modified tetrahydropyrans include but are not limited to hexitol nucleic acid (“HNA”), anitol nucleic acid (“ANA”), manitol nucleic acid (“NINA”) (see, e.g., Leumann, CJ. Bioorg. & Med. Chem. 2002, 10, 841-854), fluoro HNA:

-   -   (“F-HNA”, see e.g. Swayze et al., U.S. Pat. No. 8,088,904;         Swayze et al., U.S. Pat. No. 8,440,803; Swayze et al., U.S. Pat.         No. 8,796,437; and Swayze et al., U.S. Pat. No. 9,005,906; F-HNA         can also be referred to as a F-THP or 3′-fluoro         tetrahydropyran), and nucleosides comprising additional modified         THP compounds having the formula:

-   -   wherein, independently, for each of the modified THP         nucleosides:         -   Bx is a nucleobase moiety;         -   T₃ and T₄ are each, independently, an internucleoside             linking group linking the modified THP nucleoside to the             remainder of an oligonucleotide or one of T₃ and T₄ is an             internucleoside linking group linking the modified THP             nucleoside to the remainder of an oligonucleotide and the             other of T₃ and T₄ is H, a hydroxyl protecting group, a             linked conjugate group, or a 5′ or 3′-terminal group;     -   q₁, q₂, q₃, q₄, q₅, q₆ and q₇ are each, independently, H, C₁-C₆         alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆         alkenyl, C₂-C₆ alkynyl, or substituted C₂-C₆ alkynyl; and         -   each of R₁ and R₂ is independently selected from among:             hydrogen, halogen, substituted or unsubstituted alkoxy,             NJ₁J₂, SJ₁, N₃, OC(═X)J₁, OC(═X)NJ₁J₂, NJ₃C(═X)NJ₁J₂, and             CN, wherein X is O, S or NJ₁, and each J₁, J₂, and J₃ is,             independently, H or C₁-C₆ alkyl.

In certain embodiments, modified THP nucleosides are provided wherein q₁, q₂, q₃, q₄, q₅, q₆ and q are each H.

In certain embodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is other than H. In certain embodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆ and g₇ is methyl. In certain embodiments, modified THP nucleosides are provided wherein one of R₁ and R₂ is F. In certain embodiments, R₁ is F and R₂ is H, in certain embodiments, R₁ is methoxy and R₂ is H, and in certain embodiments, R₁ is methoxyethoxy and R₂ is H.

In certain embodiments, sugar surrogates comprise rings having more than 5 atoms and more than one heteroatom. For example, nucleosides comprising morpholino sugar moieties and their use in oligonucleotides have been reported (see, e.g., Braasch et al., Biochemistry, 2002, 41, 4503-4510 and Summerton et al., U.S. Pat. No. 5,698,685; Summerton et al., U.S. Pat. No. 5,166,315; Summerton et al., U.S. Pat. No. 5,185,444; and Summerton et al., U.S. Pat. No. 5,034,506). As used here, the term “morpholino” means a sugar surrogate having the following structure:

In certain embodiments, morpholinos may be modified, for example by adding or altering various substituent groups from the above morpholino structure. Such sugar surrogates are referred to herein as “modified morpholinos.”

In certain embodiments, sugar surrogates comprise acyclic moieties. Examples of nucleosides and oligonucleotides comprising such acyclic sugar surrogates include but are not limited to: peptide nucleic acid (“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., WO2011/133876.

Many other bicyclic and tricyclic sugar and sugar surrogate ring systems are known in the art that can be used in modified nucleosides.

2. Certain Modified Nucleobases

In certain embodiments, modified oligonucleotides comprise one or more nucleosides comprising an unmodified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside that does not comprise a nucleobase, referred to as an abasic nucleoside.

In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and 0-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 2-aminopropyladenine, 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (—C═C—CH₃) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazine-2-one, 1,3-diazaphenothiazine-2-one and 9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in Merigan et al., U.S. Pat. No. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, Kroschwitz, J. I., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y. S., Chapter 15, Antisense Research and Applications, Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; and those disclosed in Chapters 6 and 15, Antisense Drug Technology, Crooke S. T., Ed., CRC Press, 2008, 163-166 and 442-443.

Publications that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include without limitation, Manoharan et al., US2003/0158403; Manoharan et al., US2003/0175906; Dinh et al., U.S. Pat. No. 4,845,205; Spielvogel et al., U.S. Pat. No. 5,130,302; Rogers et al., U.S. Pat. No. 5,134,066; Bischofberger et al., U.S. Pat. No. 5,175,273; Urdea et al., U.S. Pat. No. 5,367,066; Benner et al., U.S. Pat. No. 5,432,272; Matteucci et al., U.S. Pat. No. 5,434,257; Gmeiner et al., U.S. Pat. No. 5,457,187; Cook et al., U.S. Pat. No. 5,459,255; Froehler et al., U.S. Pat. No. 5,484,908; Matteucci et al., U.S. Pat. No. 5,502,177; Hawkins et al., U.S. Pat. No. 5,525,711; Haralambidis et al., U.S. Pat. No. 5,552,540; Cook et al., U.S. Pat. No. 5,587,469; Froehler et al., U.S. Pat. No. 5,594,121; Switzer et al., U.S. Pat. No. 5,596,091; Cook et al., U.S. Pat. No. 5,614,617; Froehler et al., U.S. Pat. No. 5,645,985; Cook et al., U.S. Pat. No. 5,681,941; Cook et al., U.S. Pat. No. 5,811,534; Cook et al., U.S. Pat. No. 5,750,692; Cook et al., U.S. Pat. No. 5,948,903; Cook et al., U.S. Pat. No. 5,587,470; Cook et al., U.S. Pat. No. 5,457,191; Matteucci et al., U.S. Pat. No. 5,763,588; Froehler et al., U.S. Pat. No. 5,830,653; Cook et al., U.S. Pat. No. 5,808,027; Cook et al., 6,166,199; and Matteucci et al., U.S. Pat. No. 6,005,096.

3. Certain Modified Internucleoside Linkages

In certain embodiments, nucleosides of modified oligonucleotides may be linked together using any internucleoside linkage. The two main classes of internucleoside linking groups are defined by the presence or absence of a phosphorus atom. Representative phosphorus-containing internucleoside linkages include but are not limited to phosphodiesters, which contain a phosphodiester bond (“P(O₂)═O”) (also referred to as unmodified or naturally occurring linkages), phosphotriesters, methylphosphonates, phosphoramidates, phosphorothioates (“P(O₂)═S”), and phosphorodithioates (“HS—P═S”). Representative non-phosphorus containing internucleoside linking groups include but are not limited to methylenemethylimino (—CH₂—N(CH₃)—O—CH₂—), thiodiester, thionocarbamate (—O—C(═O)(NH)—S—); siloxane (—O—SiH₂—O—); and N,N′-dimethylhydrazine (—CH₂—N(CH₃)—N(CH₃)—). Modified internucleoside linkages, compared to naturally occurring phosphodiester internucleoside linkages, can be used to alter, typically increase, nuclease resistance of the oligonucleotide. In certain embodiments, internucleoside linkages having a chiral atom can be prepared as a racemic mixture, or as separate enantiomers. Methods of preparation of phosphorous-containing and non-phosphorous-containing internucleoside linkages are well known to those skilled in the art.

Representative internucleoside linkages having a chiral center include but are not limited to alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having a chiral center can be prepared as populations of modified oligonucleotides comprising stereorandom internucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate internucleoside linkages in particular stereochemical configurations. In certain embodiments, populations of modified oligonucleotides comprise phosphorothioate internucleoside linkages wherein all of the phosphorothioate internucleoside linkages are stereorandom. Such modified oligonucleotides can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate internucleoside linkage. Nonetheless, as is well understood by those of skill in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereoconfiguration. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more particular phosphorothioate internucleoside linkage in a particular, independently selected stereochemical configuration. In certain embodiments, the particular configuration of the particular phosphorothioate internucleoside linkage is present in at least 65% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate internucleoside linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate internucleoside linkage is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate internucleoside linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate internucleoside linkage is present in at least 99% of the molecules in the population. Such chirally enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, e.g., methods described in Oka et al., JACS 2003, 125, 8307, Wan et al. Nuc. Acid. Res., 2014, 42, 13456, and WO 2017/015555. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) configuration. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration. In certain embodiments, modified oligonucleotides comprising (Rp) and/or (Sp) phosphorothioates comprise one or more of the following formulas, respectively, wherein “B” indicates a nucleobase:

Unless otherwise indicated, chiral internucleoside linkages of modified oligonucleotides described herein can be stereorandom or in a particular stereochemical configuration.

Neutral internucleoside linkages include, without limitation, phosphotriesters, methylphosphonates, MMI (3′-CH₂—N(CH₃)—O-5′), amide-3 (3′-CH₂—C(═O)—N(H)-5′), amide-4 (3′-CH₂—N(H)—C(═O)-5′), formacetal (3′-O—CH₂—O-5′), methoxypropyl (MOP), and thioformacetal (3′-S—CH₂—O—5′). Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See for example: Carbohydrate Modifications in Antisense Research; Y. S. Sanghvi and P. D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral internucleoside linkages include nonionic linkages comprising mixed N, O, S and CH₂ component parts.

B. Certain Motifs

In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more modified internucleoside linkage. In such embodiments, the modified, unmodified, and differently modified sugar moieties, nucleobases, and/or internucleoside linkages of a modified oligonucleotide define a pattern or motif. In certain embodiments, the patterns of sugar moieties, nucleobases, and internucleoside linkages are each independent of one another. Thus, a modified oligonucleotide may be described by its sugar motif, nucleobase motif and/or internucleoside linkage motif (as used herein, nucleobase motif describes the modifications to the nucleobases independent of the sequence of nucleobases).

1. Certain Sugar Motifs

In certain embodiments, oligonucleotides comprise one or more type of modified sugar and/or unmodified sugar moiety arranged along the oligonucleotide or portion thereof in a defined pattern or sugar motif. In certain instances, such sugar motifs include but are not limited to any of the sugar modifications discussed herein.

In certain embodiments, modified oligonucleotides have a gapmer motif, which is defined by two external regions or “wings” and a central or internal region or “gap.” The three regions of a gapmer motif (the 5′-wing, the gap, and the 3′-wing) form a contiguous sequence of nucleosides wherein at least some of the sugar moieties of the nucleosides of each of the wings differ from at least some of the sugar moieties of the nucleosides of the gap. Specifically, at least the sugar moieties of the nucleosides of each wing that are closest to the gap (the 3′-most nucleoside of the 5′-wing and the 5′-most nucleoside of the 3′-wing) differ from the sugar moiety of the neighboring gap nucleosides, thus defining the boundary between the wings and the gap (i.e., the wing/gap junction). In certain embodiments, the sugar moieties within the gap are the same as one another. In certain embodiments, the gap includes one or more nucleoside having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the gap. In certain embodiments, the sugar motifs of the two wings are the same as one another (symmetric gapmer). In certain embodiments, the sugar motif of the 5′-wing differs from the sugar motif of the 3′-wing (asymmetric gapmer).

In certain embodiments, the wings of a gapmer comprise 1-6 nucleosides. In certain embodiments, each nucleoside of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least one nucleoside of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least two nucleosides of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least three nucleosides of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least four nucleosides of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least five nucleosides of each wing of a gapmer comprises a modified sugar moiety.

In certain embodiments, the gap of a gapmer comprises 7-12 nucleosides. In certain embodiments, each nucleoside of the gap of a gapmer comprises a 2′-deoxyribosyl sugar moiety. In certain embodiments, at least six nucleosides of the gap of a gapmer comprise a 2′-β-D-deoxyribosyl sugar moiety. In certain embodiments, each nucleoside of the gap of a gapmer comprises a 2′-β-D-deoxyribosyl sugar moiety. In certain embodiments, at least one nucleoside of the gap of a gapmer comprises a modified sugar moiety. In certain embodiments, at least one nucleoside of the gap of a gapmer comprises a 2′-OMe sugar moiety.

In certain embodiments, the gapmer is a deoxy gapmer. In certain embodiments, the nucleosides on the gap side of each wing/gap junction comprise 2′-deoxyribosyl sugar moieties and the nucleosides on the wing sides of each wing/gap junction comprise modified sugar moieties. In certain embodiments, at least six nucleosides of the gap of a gapmer comprise a 2′-β-D-deoxyribosyl sugar moiety. In certain embodiments, each nucleoside of the gap of a gapmer comprises a 2′-deoxyribosyl sugar moiety. In certain embodiments, each nucleoside of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, one nucleoside of the gap comprises a modified sugar moiety and each remaining nucleoside of the gap comprises a 2′-deoxyribosyl sugar moiety.

In certain embodiments, modified oligonucleotides comprise or consist of a portion having a fully modified sugar motif. In such embodiments, each nucleoside of the fully modified portion of the modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, each nucleoside of the entire modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise or consist of a portion having a fully modified sugar motif, wherein each nucleoside within the fully modified portion comprises the same modified sugar moiety, referred to herein as a uniformly modified sugar motif. In certain embodiments, a fully modified oligonucleotide is a uniformly modified oligonucleotide. In certain embodiments, each nucleoside of a uniformly modified oligonucleotide comprises the same 2′-modification.

Herein, the lengths (number of nucleosides) of the three regions of a gapmer may be provided using the notation [# of nucleosides in the 5′-wing]-[# of nucleosides in the gap]-[# of nucleosides in the 3′-wing]. Thus, a 5-10-5 gapmer consists of 5 linked nucleosides in each wing and 10 linked nucleosides in the gap. Where such nomenclature is followed by a specific modification, that modification is the modification in each sugar moiety of each wing and the gap nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety. Thus, a 5-10-5 MOE gapmer consists of 5 linked 2′-MOE nucleosides in the 5′-wing, 10 linked 2′-β-D-deoxynucleosides in the gap, and 5 linked 2′-MOE nucleosides in the 3′-wing. A 3-10-3 cEt gapmer consists of 3 linked cEt nucleosides in the 5′-wing, 10 linked 2′-β-D-deoxynucleosides in the gap, and 3 linked cEt nucleosides in the 3′-wing. A 5-8-5 gapmer consists of 5 linked nucleosides comprising a modified sugar moiety in the 5′-wing, 8 linked 2′-β-D-deoxynucleosides in the gap, and 5 linked nucleosides comprising a modified sugar moiety in the 3′-wing. A mixed wing gapmer has at least two different modified sugar moieties in the 5′- and/or the 3′-wing. A 5-8-5 or 5-8-4 mixed wing gapmer has at least two different modified sugar moieties in the 5′- and/or the 3′-wing.

In certain embodiments, modified oligonucleotides are 5-10-5 MOE gapmers. In certain embodiments, modified oligonucleotides are 4-10-6 MOE gapmers. In certain embodiments, modified oligonucleotides are 6-10-4 MOE gapmers. In certain embodiments, modified oligonucleotides are 4-8-6 MOE gapmers. In certain embodiments, modified oligonucleotides are 6-8-4 MOE gapmers. In certain embodiments, modified oligonucleotides are 5-8-5 MOE gapmers. In certain embodiments, modified oligonucleotides are X-Y-Z MOE gapmers, wherein X and Z are independently selected from 1, 2, 3, 4, 5, 6, or 7 linked 2′-MOE nucleosides and Y is selected from 7, 8, 9, 10, or 11 linked deoxynucleosides.

In certain embodiments, modified oligonucleotides have the following sugar motif (5′ to 3′): eeeeedyddddddddeeeee, eeeeeddddddddddeeeee, eeeeeeddddddddddeeee, eeeeddddddddddeeeeee, eeeeddddddddeeeeee, eeeeeeddddddddeeee, or eeeeeddddddddeeeee, wherein ‘d’ represents a 2′-deoxyribosyl sugar moiety, ‘e’ represents a 2′-MOE sugar moiety, and ‘y’ represents a 2′-OMe sugar moiety.

2. Certain Nucleobase Motifs

In certain embodiments, oligonucleotides comprise modified and/or unmodified nucleobases arranged along the oligonucleotide or portion thereof in a defined pattern or motif. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases are modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in a modified oligonucleotide are 5-methyl cytosines. In certain embodiments, all of the cytosine nucleobases are 5-methyl cytosines and all of the other nucleobases of the modified oligonucleotide are unmodified nucleobases.

In certain embodiments, modified oligonucleotides comprise a block of modified nucleobases. In certain such embodiments, the block is at the 3′-end of the oligonucleotide. In certain embodiments the block is within 3 nucleosides of the 3′-end of the oligonucleotide. In certain embodiments, the block is at the 5′-end of the oligonucleotide. In certain embodiments the block is within 3 nucleosides of the 5′-end of the oligonucleotide.

In certain embodiments, oligonucleotides having a gapmer motif comprise a nucleoside comprising a modified nucleobase. In certain such embodiments, one nucleoside comprising a modified nucleobase is in the central gap of an oligonucleotide having a gapmer motif. In certain such embodiments, the sugar moiety of the nucleoside is a 2′-β-D-deoxyribosyl sugar moiety. In certain embodiments, the modified nucleobase is selected from: a 2-thiopyrimidine and a 5-propynepyrimidine.

3. Certain Internucleoside Linkage Motifs

In certain embodiments, oligonucleotides comprise modified and/or unmodified internucleoside linkages arranged along the oligonucleotide or portion thereof in a defined pattern or motif. In certain embodiments, each internucleoside linking group is a phosphodiester internucleoside linkage (P═O). In certain embodiments, each internucleoside linking group of a modified oligonucleotide is a phosphorothioate internucleoside linkage (P═S). In certain embodiments, each internucleoside linkage of a modified oligonucleotide is independently selected from a phosphorothioate internucleoside linkage and phosphodiester internucleoside linkage. In certain embodiments, each phosphorothioate internucleoside linkage is independently selected from a stereorandom phosphorothioate, a (Sp) phosphorothioate, and a (Rp) phosphorothioate. In certain embodiments, the sugar motif of a modified oligonucleotide is a gapmer and the internucleoside linkages within the gap are all modified. In certain such embodiments, some or all of the internucleoside linkages in the wings are unmodified phosphodiester internucleoside linkages. In certain embodiments, the terminal internucleoside linkages are modified. In certain embodiments, the sugar motif of a modified oligonucleotide is a gapmer, and the internucleoside linkage motif comprises at least one phosphodiester internucleoside linkage in at least one wing, wherein the at least one phosphodiester internucleoside linkage is not a terminal internucleoside linkage, and the remaining internucleoside linkages are phosphorothioate internucleoside linkages. In certain such embodiments, all of the phosphorothioate internucleoside linkages are stereorandom. In certain embodiments, all of the phosphorothioate internucleoside linkages in the wings are (Sp) phosphorothioates, and the gap comprises at least one Sp, Sp, Rp motif. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising such internucleoside linkage motifs.

In certain embodiments, modified oligonucleotides have an internucleoside linkage motif of (5′ to 3′): sooosssssssssssssss, soooossssssssssooss, sooooossssssssssoss, sooossssssssssoooss, soosssssssssoooss, soooosssssssssoss, or sooosssssssssooss, wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

C. Certain Lengths

It is possible to increase or decrease the length of an oligonucleotide without eliminating activity. For example, in Woolf et al. (Proc. Natl. Acad. Sci. USA 89:7305-7309, 1992), a series of oligonucleotides 13-25 nucleobases in length were tested for their ability to induce cleavage of a target nucleic acid in an oocyte injection model. Oligonucleotides 25 nucleobases in length with 8 or 11 mismatch bases near the ends of the oligonucleotides were able to direct specific cleavage of the target nucleic acid, albeit to a lesser extent than the oligonucleotides that contained no mismatches. Similarly, target specific cleavage was achieved using 13 nucleobase oligonucleotides, including those with 1 or 3 mismatches.

In certain embodiments, oligonucleotides (including modified oligonucleotides) can have any of a variety of ranges of lengths. In certain embodiments, oligonucleotides consist of X to Y linked nucleosides, where X represents the fewest number of nucleosides in the range and Y represents the largest number nucleosides in the range. In certain such embodiments, X and Y are each independently selected from 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; provided that X≤Y. For example, in certain embodiments, oligonucleotides consist of 12 to 13, 12 to 14, 12 to 15, 12 to 16, 12 to 17, 12 to 18, 12 to 19, 12 to 20, 12 to 21, 12 to 22, 12 to 23, 12 to 24, 12 to 25, 12 to 26, 12 to 27, 12 to 28, 12 to 29, 12 to 30, 13 to 14, 13 to 15, 13 to 16, 13 to 17, 13 to 18, 13 to 19, 13 to 20, 13 to 21, 13 to 22, 13 to 23, 13 to 24, 13 to 25, 13 to 26, 13 to 27, 13 to 28, 13 to 29, 13 to 30, 14 to 15, 14 to 16, 14 to 17, 14 to 18, 14 to 19, 14 to 20, 14 to 21, 14 to 22, 14 to 23, 14 to 24, 14 to 25, 14 to 26, 14 to 27, 14 to 28, 14 to 29, 14 to 30, 15 to 16, 15 to 17, 15 to 18, 15 to 19, 15 to 20, 15 to 21, 15 to 22, 15 to 23, 15 to 24, 15 to 25, 15 to 26, 15 to 27, 15 to 28, 15 to 29, 15 to 30, 16 to 17, 16 to 18, 16 to 19, 16 to 20, 16 to 21, 16 to 22, 16 to 23, 16 to 24, 16 to 25, 16 to 26, 16 to 27, 16 to 28, 16 to 29, 16 to 30, 17 to 18, 17 to 19, 17 to 20, 17 to 21, 17 to 22, 17 to 23, 17 to 24, 17 to 25, 17 to 26, 17 to 27, 17 to 28, 17 to 29, 17 to 30, 18 to 19, 18 to 20, 18 to 21, 18 to 22, 18 to 23, 18 to 24, 18 to 25, 18 to 26, 18 to 27, 18 to 28, 18 to 29, 18 to 30, 19 to 20, 19 to 21, 19 to 22, 19 to 23, 19 to 24, 19 to 25, 19 to 26, 19 to 29, 19 to 28, 19 to 29, 19 to 30, 20 to 21, 20 to 22, 20 to 23, 20 to 24, 20 to 25, 20 to 26, 20 to 27, 20 to 28, 20 to 29, 20 to 30, 21 to 22, 21 to 23, 21 to 24, 21 to 25, 21 to 26, 21 to 27, 21 to 28, 21 to 29, 21 to 30, 22 to 23, 22 to 24, 22 to 25, 22 to 26, 22 to 27, 22 to 28, 22 to 29, 22 to 30, 23 to 24, 23 to 25, 23 to 26, 23 to 27, 23 to 28, 23 to 29, 23 to 30, 24 to 25, 24 to 26, 24 to 27, 24 to 28, 24 to 29, 24 to 30, 25 to 26, 25 to 27, 25 to 28, 25 to 29, 25 to 30, 26 to 27, 26 to 28, 26 to 29, 26 to 30, 27 to 28, 27 to 29, 27 to 30, 28 to 29, 28 to 30, or 29 to 30 linked nucleosides.

D. Certain Modified Oligonucleotides

In certain embodiments, the above modifications (sugar, nucleobase, internucleoside linkage) are incorporated into a modified oligonucleotide. In certain embodiments, modified oligonucleotides are characterized by their modification motifs and overall lengths. In certain embodiments, such parameters are each independent of one another. Thus, unless otherwise indicated, each internucleoside linkage of an oligonucleotide having a gapmer sugar motif may be modified or unmodified and may or may not follow the gapmer modification pattern of the sugar modifications. For example, the internucleoside linkages within the wing regions of a sugar gapmer may be the same or different from one another and may be the same or different from the internucleoside linkages of the gap region of the sugar motif. Likewise, such sugar gapmer oligonucleotides may comprise one or more modified nucleobase independent of the gapmer pattern of the sugar modifications. Unless otherwise indicated, all modifications are independent of nucleobase sequence.

E. Certain Populations of Modified Oligonucleotides

Populations of modified oligonucleotides in which all of the modified oligonucleotides of the population have the same molecular formula can be stereorandom populations or chirally enriched populations. All of the chiral centers of all of the modified oligonucleotides are stereorandom in a stereorandom population. In a chirally enriched population, at least one particular chiral center is not stereorandom in the modified oligonucleotides of the population. In certain embodiments, the modified oligonucleotides of a chirally enriched population are enriched for β-D ribosyl sugar moieties, and all of the phosphorothioate internucleoside linkages are stereorandom. In certain embodiments, the modified oligonucleotides of a chirally enriched population are enriched for both β-D ribosyl sugar moieties and at least one, particular phosphorothioate internucleoside linkage in a particular stereochemical configuration.

F. Nucleobase Sequence

In certain embodiments, oligonucleotides (unmodified or modified oligonucleotides) are further described by their nucleobase sequence. In certain embodiments oligonucleotides have a nucleobase sequence that is complementary to a second oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid. In certain such embodiments, a portion of an oligonucleotide has a nucleobase sequence that is complementary to a second oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid. In certain embodiments, the nucleobase sequence of a portion or entire length of an oligonucleotide is at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the second oligonucleotide or nucleic acid, such as a target nucleic acid.

II. Certain Oligomeric Compounds

In certain embodiments, provided herein are oligomeric compounds, which consist of an oligonucleotide (modified or unmodified) and optionally one or more conjugate groups and/or terminal groups. Conjugate groups consist of one or more conjugate moiety and a conjugate linker which links the conjugate moiety to the oligonucleotide. Conjugate groups may be attached to either or both ends of an oligonucleotide and/or at any internal position. In certain embodiments, conjugate groups are attached to the 2′-position of a nucleoside of a modified oligonucleotide. In certain embodiments, conjugate groups that are attached to either or both ends of an oligonucleotide are terminal groups. In certain such embodiments, conjugate groups or terminal groups are attached at the 3′ and/or 5′-end of oligonucleotides. In certain such embodiments, conjugate groups (or terminal groups) are attached at the 3′-end of oligonucleotides. In certain embodiments, conjugate groups are attached near the 3′-end of oligonucleotides. In certain embodiments, conjugate groups (or terminal groups) are attached at the 5′-end of oligonucleotides. In certain embodiments, conjugate groups are attached near the 5′-end of oligonucleotides.

Examples of terminal groups include but are not limited to conjugate groups, capping groups, phosphate moieties, protecting groups, abasic nucleosides, modified or unmodified nucleosides, and two or more nucleosides that are independently modified or unmodified.

A. Certain Conjugate Groups

In certain embodiments, oligonucleotides are covalently attached to one or more conjugate groups. In certain embodiments, conjugate groups modify one or more properties of the attached oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance. In certain embodiments, conjugate groups impart a new property on the attached oligonucleotide, e.g., fluorophores or reporter groups that enable detection of the oligonucleotide. Certain conjugate groups and conjugate moieties have been described previously, for example: cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Lett., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N. Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Lett., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g., do-decan-diol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), or adamantane acetic acid a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229-237), an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937), a tocopherol group (Nishina et al., Molecular Therapy Nucleic Acids, 2015, 4, e220; and Nishina et al., Molecular Therapy, 2008, 16, 734-740), or a N-acetylgalactosamine (GalNAc) cluster (e.g., WO2014/179620).

In certain embodiments, conjugate groups may be selected from any of a C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, C5 alkyl, C22 alkenyl, C20 alkenyl, C16 alkenyl, C10 alkenyl, C21 alkenyl, C19 alkenyl, C18 alkenyl, C15 alkenyl, C14 alkenyl, C13 alkenyl, C12 alkenyl, C11 alkenyl, C9 alkenyl, C8 alkenyl, C7 alkenyl, C6 alkenyl, or C5 alkenyl.

In certain embodiments, conjugate groups may be selected from any of C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, and C5 alkyl, where the alkyl chain has one or more unsaturated bonds.

1. Conjugate Moieties

Conjugate moieties include, without limitation, intercalators, reporter molecules, polyamines, polyamides, peptides, carbohydrates, vitamin moieties, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic acid moieties, folate, lipids, lipophilic groups, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores, and dyes.

In certain embodiments, a conjugate moiety comprises an active drug substance, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indo-methicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic.

2. Conjugate Linkers

Conjugate moieties are attached to oligonucleotides through conjugate linkers. In certain oligomeric compounds, the conjugate linker is a single chemical bond (i.e., the conjugate moiety is attached directly to an oligonucleotide through a single bond). In certain oligomeric compounds, a conjugate moiety is attached to an oligonucleotide via a more complex conjugate linker comprising one or more conjugate linker moieties, which are sub-units making up a conjugate linker. In certain embodiments, the conjugate linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units such as ethylene glycol, nucleosides, or amino acid units.

In certain embodiments, a conjugate linker comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain such embodiments, the conjugate linker comprises groups selected from alkyl, amino, oxo, amide and ether groups. In certain embodiments, the conjugate linker comprises groups selected from alkyl and amide groups. In certain embodiments, the conjugate linker comprises groups selected from alkyl and ether groups. In certain embodiments, the conjugate linker comprises at least one phosphorus moiety. In certain embodiments, the conjugate linker comprises at least one phosphate group. In certain embodiments, the conjugate linker includes at least one neutral linking group.

In certain embodiments, conjugate linkers, including the conjugate linkers described above, are bifunctional linking moieties, e.g., those known in the art to be useful for attaching conjugate groups to parent compounds, such as the oligonucleotides provided herein. In general, a bifunctional linking moiety comprises at least two functional groups. One of the functional groups is selected to bind to a particular site on a parent compound and the other is selected to bind to a conjugate group. Examples of functional groups used in a bifunctional linking moiety include but are not limited to electrophiles for reacting with nucleophilic groups and nucleophiles for reacting with electrophilic groups. In certain embodiments, bifunctional linking moieties comprise one or more groups selected from amino, hydroxyl, carboxylic acid, thiol, alkyl, alkenyl, and alkynyl.

Examples of conjugate linkers include but are not limited to pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) and 6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include but are not limited to substituted or unsubstituted C₁-C₁₀ alkyl, substituted or unsubstituted C₂-C₁₀ alkenyl or substituted or unsubstituted C₂-C₁₀ alkynyl, wherein a nonlimiting list of preferred substituent groups includes hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl and alkynyl.

In certain embodiments, conjugate linkers comprise 1-10 linker-nucleosides. In certain embodiments, conjugate linkers comprise 2-5 linker-nucleosides. In certain embodiments, conjugate linkers comprise exactly 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise the TCA motif. In certain embodiments, such linker-nucleosides are modified nucleosides. In certain embodiments such linker-nucleosides comprise a modified sugar moiety. In certain embodiments, linker-nucleosides are unmodified. In certain embodiments, linker-nucleosides comprise an optionally protected heterocyclic base selected from a purine, substituted purine, pyrimidine or substituted pyrimidine. In certain embodiments, a cleavable moiety is a nucleoside selected from uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methyl cytosine, 4-N-benzoyl-5-methyl cytosine, adenine, 6-N-benzoyladenine, guanine and 2-N-isobutyrylguanine. It is typically desirable for linker-nucleosides to be cleaved from the oligomeric compound after it reaches a target tissue. Accordingly, linker-nucleosides are typically linked to one another and to the remainder of the oligomeric compound through cleavable bonds. In certain embodiments, such cleavable bonds are phosphodiester bonds.

Herein, linker-nucleosides are not considered to be part of the oligonucleotide. Accordingly, in embodiments in which an oligomeric compound comprises an oligonucleotide consisting of a specified number or range of linked nucleosides and/or a specified percent complementarity to a reference nucleic acid and the oligomeric compound also comprises a conjugate group comprising a conjugate linker comprising linker-nucleosides, those linker-nucleosides are not counted toward the length of the oligonucleotide and are not used in determining the percent complementarity of the oligonucleotide for the reference nucleic acid. For example, an oligomeric compound may comprise (1) a modified oligonucleotide consisting of 8-30 nucleosides and (2) a conjugate group comprising 1-10 linker-nucleosides that are contiguous with the nucleosides of the modified oligonucleotide. The total number of contiguous linked nucleosides in such an oligomeric compound is more than 30. Alternatively, an oligomeric compound may comprise a modified oligonucleotide consisting of 8-30 nucleosides and no conjugate group. The total number of contiguous linked nucleosides in such an oligomeric compound is no more than 30. Unless otherwise indicated conjugate linkers comprise no more than 10 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 5 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 2 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 1 linker-nucleoside.

In certain embodiments, it is desirable for a conjugate group to be cleaved from the oligonucleotide. For example, in certain circumstances oligomeric compounds comprising a particular conjugate moiety are better taken up by a particular cell type, but once the oligomeric compound has been taken up, it is desirable that the conjugate group be cleaved to release the unconjugated or parent oligonucleotide. Thus, certain conjugate linkers may comprise one or more cleavable moieties. In certain embodiments, a cleavable moiety is a cleavable bond. In certain embodiments, a cleavable moiety is a group of atoms comprising at least one cleavable bond. In certain embodiments, a cleavable moiety comprises a group of atoms having one, two, three, four, or more than four cleavable bonds. In certain embodiments, a cleavable moiety is selectively cleaved inside a cell or subcellular compartment, such as a lysosome. In certain embodiments, a cleavable moiety is selectively cleaved by endogenous enzymes, such as nucleases.

In certain embodiments, a cleavable bond is selected from among: an amide, an ester, an ether, one or both esters of a phosphodiester, a phosphate ester, a carbamate, or a disulfide. In certain embodiments, a cleavable bond is one or both of the esters of a phosphodiester. In certain embodiments, a cleavable moiety comprises a phosphate or phosphodiester. In certain embodiments, the cleavable moiety is a phosphate or phosphodiester linkage between an oligonucleotide and a conjugate moiety or conjugate group.

In certain embodiments, a cleavable moiety comprises or consists of one or more linker-nucleosides. In certain such embodiments, the one or more linker-nucleosides are linked to one another and/or to the remainder of the oligomeric compound through cleavable bonds. In certain embodiments, such cleavable bonds are unmodified phosphodiester bonds. In certain embodiments, a cleavable moiety is 2′-deoxynucleoside that is attached to either the 3′ or 5-terminal nucleoside of an oligonucleotide by a phosphodiester internucleoside linkage and covalently attached to the remainder of the conjugate linker or conjugate moiety by a phosphate or phosphorothioate internucleoside linkage. In certain such embodiments, the cleavable moiety is 2′-deoxyadenosine.

3. Cell-Targeting Moieties

In certain embodiments, a conjugate group comprises a cell-targeting moiety. In certain embodiments, a conjugate group has the general formula:

-   -   wherein n is from 1 to about 3, m is 0 when n is 1, m is 1 when         n is 2 or greater, j is 1 or 0, and k is 1 or 0.

In certain embodiments, n is 1, j is 1 and k is 0. In certain embodiments, n is 1, j is 0 and k is 1. In certain embodiments, n is 1, j is 1 and k is 1. In certain embodiments, n is 2, j is 1 and k is 0. In certain embodiments, n is 2, j is 0 and k is 1. In certain embodiments, n is 2, j is 1 and k is 1. In certain embodiments, n is 3, j is 1 and k is 0. In certain embodiments, n is 3, j is 0 and k is 1. In certain embodiments, n is 3, j is 1 and k is 1.

In certain embodiments, conjugate groups comprise cell-targeting moieties that have at least one tethered ligand. In certain embodiments, cell-targeting moieties comprise two tethered ligands covalently attached to a branching group. In certain embodiments, cell-targeting moieties comprise three tethered ligands covalently attached to a branching group.

B. Certain Terminal Groups

In certain embodiments, oligomeric compounds comprise one or more terminal groups. In certain such embodiments, oligomeric compounds comprise a stabilized 5′-phosphate. Stabilized 5′-phosphates include, but are not limited to 5′-phosphonates, including, but not limited to 5′-vinylphosphonates. In certain embodiments, terminal groups comprise one or more abasic nucleosides and/or inverted nucleosides. In certain embodiments, terminal groups comprise one or more 2′-linked nucleosides. In certain such embodiments, the 2′-linked nucleoside is an abasic nucleoside.

III. Oligomeric Duplexes

In certain embodiments, oligomeric compounds described herein comprise an oligonucleotide, having a nucleobase sequence complementary to that of a target nucleic acid. In certain embodiments, an oligomeric compound is paired with a second oligomeric compound to form an oligomeric duplex. Such oligomeric duplexes comprise a first oligomeric compound having a portion complementary to a target nucleic acid and a second oligomeric compound having a portion complementary to the first oligomeric compound. In certain embodiments, the first oligomeric compound of an oligomeric duplex comprises or consists of (1) a modified or unmodified oligonucleotide and optionally a conjugate group and (2) a second modified or unmodified oligonucleotide and optionally a conjugate group. Either or both oligomeric compounds of an oligomeric duplex may comprise a conjugate group. The oligonucleotides of each oligomeric compound of an oligomeric duplex may include non-complementary overhanging nucleosides.

IV. Antisense Activity

In certain embodiments, oligomeric compounds and oligomeric duplexes are capable of hybridizing to a target nucleic acid, resulting in at least one antisense activity; such oligomeric compounds and oligomeric duplexes are antisense compounds. In certain embodiments, antisense compounds have antisense activity when they reduce the amount or activity of a target nucleic acid by 25% or more in the standard cell assay. In certain embodiments, antisense compounds selectively affect one or more target nucleic acid. Such antisense compounds comprise a nucleobase sequence that hybridizes to one or more target nucleic acid, resulting in one or more desired antisense activity and does not hybridize to one or more non-target nucleic acid or does not hybridize to one or more non-target nucleic acid in such a way that results in significant undesired antisense activity.

In certain antisense activities, hybridization of an antisense compound to a target nucleic acid results in recruitment of a protein that cleaves the target nucleic acid. For example, certain antisense compounds result in RNase H mediated cleavage of the target nucleic acid. RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex. The DNA in such an RNA:DNA duplex need not be unmodified DNA. In certain embodiments, described herein are antisense compounds that are sufficiently “DNA-like” to elicit RNase H activity. In certain embodiments, one or more non-DNA-like nucleoside in the gap of a gapmer is tolerated.

In certain antisense activities, an antisense compound or a portion of an antisense compound is loaded into an RNA-induced silencing complex (RISC), ultimately resulting in cleavage of the target nucleic acid. For example, certain antisense compounds result in cleavage of the target nucleic acid by Argonaute. Antisense compounds that are loaded into RISC are RNAi compounds. RNAi compounds may be double-stranded (siRNA) or single-stranded (ssRNA).

In certain embodiments, hybridization of an antisense compound to a target nucleic acid does not result in recruitment of a protein that cleaves that target nucleic acid. In certain embodiments, hybridization of the antisense compound to the target nucleic acid results in alteration of splicing of the target nucleic acid. In certain embodiments, hybridization of an antisense compound to a target nucleic acid results in inhibition of a binding interaction between the target nucleic acid and a protein or other nucleic acid. In certain embodiments, hybridization of an antisense compound to a target nucleic acid results in alteration of translation of the target nucleic acid.

Antisense activities may be observed directly or indirectly. In certain embodiments, observation or detection of an antisense activity involves observation or detection of a change in an amount of a target nucleic acid or protein encoded by such target nucleic acid, a change in the ratio of splice variants of a nucleic acid or protein and/or a phenotypic change in a cell or subject.

V. Certain Target Nucleic Acids

In certain embodiments, oligomeric compounds comprise or consist of an oligonucleotide comprising a portion that is complementary to a target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid encodes a protein. In certain such embodiments, the target nucleic acid is selected from: a mature mRNA and a pre-mRNA, including intronic, exonic and untranslated regions. In certain embodiments, the target nucleic acid is a mature mRNA. In certain embodiments, the target nucleic acid is a pre-mRNA. In certain embodiments, the target region is entirely within an intron. In certain embodiments, the target region spans an intron/exon junction. In certain embodiments, the target region is at least 50% within an intron.

A. Complementarity/Mismatches to the Target Nucleic Acid

It is possible to introduce mismatch bases without eliminating activity. For example, Gautschi et al (J. Natl. Cancer Inst. 93:463-471, March 2001) demonstrated the ability of an oligonucleotide having 100% complementarity to the bcl-2 mRNA and having 3 mismatches to the bcl-xL mRNA to reduce the expression of both bcl-2 and bcl-xL in vitro and in vivo. Furthermore, this oligonucleotide demonstrated potent anti-tumor activity in vivo. Maher and Dolnick (Nuc. Acid. Res. 16:3341-3358, 1988) tested a series of tandem 14 nucleobase oligonucleotides, and 28 and 42 nucleobase oligonucleotides comprised of the sequence of two or three of the tandem oligonucleotides, respectively, for their ability to arrest translation of human DHFR in a rabbit reticulocyte assay. Each of the three 14 nucleobase oligonucleotides alone was able to inhibit translation, albeit at a more modest level than the 28 or 42 nucleobase oligonucleotides.

In certain embodiments, oligonucleotides are complementary to the target nucleic acid over the entire length of the oligonucleotide. In certain embodiments, oligonucleotides are 99%, 95%, 90%, 85%, or 80% complementary to the target nucleic acid. In certain embodiments, oligonucleotides are at least 80% complementary to the target nucleic acid over the entire length of the oligonucleotide and comprise a portion that is 100% or fully complementary to a target nucleic acid. In certain embodiments, the portion of full complementarity is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 nucleobases in length.

In certain embodiments, oligonucleotides comprise one or more mismatched nucleobases relative to the target nucleic acid. In certain embodiments, antisense activity against the target is reduced by such mismatch, but activity against a non-target is reduced by a greater amount. Thus, in certain embodiments selectivity of the oligonucleotide is improved. In certain embodiments, the mismatch is specifically positioned within an oligonucleotide having a gapmer motif. In certain embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 from the 5′-end of the gap region. In certain embodiments, the mismatch is at position 1, 2, 3, 4, 5, or 6 from the 5′-end of the 5′ wing region or the 3′ wing region.

B. SCN2A

In certain embodiments, oligomeric compounds comprise or consist of an oligonucleotide that is complementary to a target nucleic acid, wherein the target nucleic acid is an SCN2A nucleic acid. In certain embodiments, the SCN2A nucleic acid has the sequence set forth in SEQ ID NO: 1 (GENBANK Accession No. NM_001040142.2) or SEQ ID NO: 2 (GENBANK Accession No. NC_000002.12 truncated from nucleotides 165127001 to 165395000).

In certain embodiments, contacting a cell with an oligomeric compound complementary to SEQ ID NO: 1 or SEQ ID NO: 2 reduces the amount of SCN2A RNA in a cell, and in certain embodiments reduces the amount of SCN1A protein in a cell. In certain embodiments, contacting a cell with a modified oligonucleotide complementary to SEQ ID NO: 1 or SEQ ID NO: 2 reduces the amount of SCN2A RNA in a cell, and in certain embodiments reduces the amount of SCN2A protein in a cell. In certain embodiments, the cell is in vitro. In certain embodiments, the cell is in a subject. In certain embodiments, the oligomeric compound consists of a modified oligonucleotide. In certain embodiments, contacting a cell in a subject with an oligomeric compound complementary to SEQ ID NO: 1 or SEQ ID NO: 2 ameliorates one or more symptoms or hallmarks of a disease or disorder associated with a voltage-gated sodium channel protein. In certain embodiments, the voltage-gated sodium channel protein is SCN2A. In certain embodiments, the subject has a disease or disorder associated with a voltage-gated sodium channel protein that is not SCN2A In certain embodiments, the subject has a disease or disorder associated with SCN1A. In certain embodiments, the disease or disorder is a Developmental or Epileptic Encephalopathy, such as Early Seizure Onset Epileptic Encephalopathy, Late Seizure Onset Epileptic or Encephalopathy, Benign Familial Neonatal-Infantile Seizures; in certain embodiments, the disease or disorder is an intellectual disability or an autism spectrum disorder; in certain embodiments, the disease or disorder is Dravet Syndrome.

In certain embodiments, the symptom or hallmark is any of seizures, hypotonia, sensory integration disorders, motor dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, visual dysfunctions, delayed language and speech, gastrointestinal disorders for example, gastroesophageal reflux, diarrhea, constipation, dysmotility, and the like), neurodevelopmental delays, sudden unexpected death in epilepsy, motor development delays, delayed social and language milestones, repetitive actions, uncoordinated oral movements, and sleep problems. In certain embodiments, the seizures are any of focal, clonic, tonic, and generalized tonic and clonic seizures, prolonged seizures (often lasting longer than 10 minutes), and frequent seizures (for example, convulsive, myoclonic, absence, focal, obtundation status, and tonic seizures).

In certain embodiments, an oligomeric compound complementary to SEQ ID NO: 1 or SEQ ID NO: 2 is capable of reducing the detectable amount of SCN2A RNA in vitro by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% in the standard in vitro assay. In certain embodiments, an oligomeric compound complementary to SEQ ID NO: 1 or SEQ ID NO: 2 is capable of reducing the detectable amount of SCN2A protein in vitro by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% in the standard in vitro assay. In certain embodiments, an oligomeric compound complementary to SEQ ID NO: 1 or SEQ ID NO: 2 is capable of reducing the detectable amount of SCN2A RNA in vivo by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% when administered according to the standard in vivo assay. In certain embodiments, an oligomeric compound complementary to SEQ ID NO: 1 or SEQ ID NO: 2 is capable of reducing the detectable amount of SCN2A protein in vivo by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% when administered according to the standard in vivo assay. In certain embodiments, an oligomeric compound complementary to SEQ ID NO: 1 or SEQ ID NO: 2, is capable of reducing the detectable amount of SCN2A RNA in the CSF of a subject by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In certain embodiments, an oligomeric compound complementary to SEQ ID NO: 1 or SEQ ID NO: 2, is capable of reducing the detectable amount of SCN2A protein in the CSF of a subject by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

In certain embodiments, oligomeric compounds do not comprise a bicyclic sugar moiety. In certain embodiments, oligomeric compounds do not comprise more than one, two, three, four, five, six, seven, eight, or nine bicyclic sugar moieties. In certain embodiments, oligomeric compounds comprise one or two wing segments that comprise a nucleoside that is not a bicyclic nucleoside. In certain embodiments, oligomeric compounds do not comprise a LNA sugar moiety. In certain embodiments, oligomeric compounds do not comprise more than one, two, three, four, five, six, seven, eight, or nine LNA sugar moieties. In certain embodiments, oligomeric compounds comprise one or two wing segments that comprise a nucleoside that is not a LNA nucleoside.

Certain Target Nucleic Acids in Certain Tissues

In certain embodiments, oligomeric compounds comprise or consist of an oligonucleotide comprising a portion that is complementary to a target nucleic acid, wherein the target nucleic acid is expressed in a pharmacologically relevant tissue. In certain embodiments, the pharmacologically relevant tissues are the cells and tissues that comprise the central nervous system. Such tissues include the cortex, hippocampus, and spinal cord.

VI. Certain Pharmaceutical Compositions

In certain embodiments, described herein are pharmaceutical compositions comprising one or more oligomeric compounds. In certain embodiments, the one or more oligomeric compounds each consists of a modified oligonucleotide. In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable diluent or carrier. In certain embodiments, a pharmaceutical composition comprises or consists of a sterile saline solution and one or more oligomeric compound. In certain embodiments, the sterile saline is pharmaceutical grade saline. In certain embodiments, a pharmaceutical composition comprises or consists of one or more oligomeric compound and sterile water. In certain embodiments, the sterile water is pharmaceutical grade water. In certain embodiments, a pharmaceutical composition comprises or consists of one or more oligomeric compound and phosphate-buffered saline (PBS). In certain embodiments, the sterile PBS is pharmaceutical grade PBS. In certain embodiments, a pharmaceutical composition comprises or consists of one or more oligomeric compound and artificial cerebrospinal fluid (“artificial CSF” or “aCSF”). In certain embodiments, the artificial cerebrospinal fluid is pharmaceutical grade.

In certain embodiments, a pharmaceutical composition comprises a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, a pharmaceutical composition consists of a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, a pharmaceutical composition consists essentially of a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, the artificial cerebrospinal fluid is pharmaceutical grade.

In certain embodiments, pharmaceutical compositions comprise one or more oligomeric compound and one or more excipients. In certain embodiments, excipients are selected from water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.

In certain embodiments, oligomeric compounds may be admixed with pharmaceutically acceptable active and/or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions depend on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

In certain embodiments, pharmaceutical compositions comprising an oligomeric compound encompass any pharmaceutically acceptable salts of the oligomeric compound, esters of the oligomeric compound, or salts of such esters. In certain embodiments, pharmaceutical compositions comprising oligomeric compounds comprising one or more oligonucleotide, upon administration to a subject, including a human, are capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of oligomeric compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts. In certain embodiments, prodrugs comprise one or more conjugate group attached to an oligonucleotide, wherein the conjugate group is cleaved by endogenous nucleases within the body.

Lipid moieties have been used in nucleic acid therapies in a variety of methods. In certain such methods, the nucleic acid, such as an oligomeric compound, is introduced into preformed liposomes or lipoplexes made of mixtures of cationic lipids and neutral lipids. In certain methods, DNA complexes with mono- or poly-cationic lipids are formed without the presence of a neutral lipid. In certain embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to a particular cell or tissue. In certain embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to fat tissue. In certain embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to muscle tissue.

In certain embodiments, pharmaceutical compositions comprise a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.

In certain embodiments, pharmaceutical compositions comprise one or more tissue-specific delivery molecules designed to deliver the one or more pharmaceutical agents comprising an oligomeric compound provided herein to specific tissues or cell types. For example, in certain embodiments, pharmaceutical compositions include liposomes coated with a tissue-specific antibody.

In certain embodiments, pharmaceutical compositions comprise a co-solvent system. Certain of such co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, such co-solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™ and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

In certain embodiments, pharmaceutical compositions are prepared for oral administration. In certain embodiments, pharmaceutical compositions are prepared for buccal administration. In certain embodiments, a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, intrathecal (IT), intracerebroventricular (ICV), intraneural, perineural, etc.). In certain of such embodiments, a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.

Under certain conditions, certain compounds disclosed herein act as acids. Although such compounds may be drawn or described in protonated (free acid) form, or ionized and in association with a cation (salt) form, aqueous solutions of such compounds exist in equilibrium among such forms. For example, a phosphate linkage of an oligonucleotide in aqueous solution exists in equilibrium among free acid, anion and salt forms. Unless otherwise indicated, compounds described herein are intended to include all such forms. Moreover, certain oligonucleotides have several such linkages, each of which is in equilibrium. Thus, oligonucleotides in solution exist in an ensemble of forms at multiple positions all at equilibrium. The term “oligonucleotide” is intended to include all such forms. Drawn structures necessarily depict a single form. Nevertheless, unless otherwise indicated, such drawings are likewise intended to include corresponding forms. Herein, a structure depicting the free acid of a compound followed by the term “or salt thereof” expressly includes all such forms that may be fully or partially protonated/de-protonated/in association with a cation. In certain instances, one or more specific cation is identified.

In certain embodiments, modified oligonucleotides or oligomeric compounds are in aqueous solution with sodium. In certain embodiments, modified oligonucleotides or oligomeric compounds are in aqueous solution with potassium. In certain embodiments, modified oligonucleotides or oligomeric compounds are in PBS. In certain embodiments, modified oligonucleotides or oligomeric compounds are in water. In certain such embodiments, the pH of the solution is adjusted with NaOH and/or HCl to achieve a desired pH.

Herein, certain specific doses are described. A dose may be in the form of a dosage unit. For clarity, a dose (or dosage unit) of a modified oligonucleotide or an oligomeric compound in milligrams indicates the mass of the free acid form of the modified oligonucleotide or oligomeric compound. As described above, in aqueous solution, the free acid is in equilibrium with anionic and salt forms. However, for the purpose of calculating dose, it is assumed that the modified oligonucleotide or oligomeric compound exists as a solvent-free, sodium-acetate free, anhydrous, free acid. For example, where a modified oligonucleotide or an oligomeric compound is in solution comprising sodium (e.g., saline), the modified oligonucleotide or oligomeric compound may be partially or fully de-protonated and in association with Na+ ions. However, the mass of the protons are nevertheless counted toward the weight of the dose, and the mass of the Na+ ions are not counted toward the weight of the dose. Thus, for example, a dose, or dosage unit, of 10 mg of Compound No. 1348259, equals the number of fully protonated molecules that weighs 10 mg. This would be equivalent to 10.59 mg of solvent-free, sodium acetate-free, anhydrous sodiated Compound No. 1348259. When an oligomeric compound comprises a conjugate group, the mass of the conjugate group is included in calculating the dose of such oligomeric compound. If the conjugate group also has an acid, the conjugate group is likewise assumed to be fully protonated for the purpose of calculating dose.

VI. Certain Compositions

1. Compound No. 1348259

In certain embodiments, Compound No. 1348259 is characterized as a 5-10-5 MOE gapmer having a sequence (from 5′ to 3′) of GCATAATCCCATTATACAAA (SEQ ID NO: 2493), wherein each of nucleosides 1-5 and 16-20 (from 5′ to 3′) are 2′-MOE nucleosides and each of nucleosides 6-15 are 2′-β-D-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 5 to 6, 16 to 17, and 17 to 18 are phosphodiester internucleoside linkages, the internucleoside linkages between nucleosides 1 to 2, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments Compound No. 1348259 is represented b the following chemical notation:

(SEQ ID NO: 2493) G_(es) ^(m)C_(eo)A_(eo)T_(eo)A_(eo)A_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(eo) ^(m)C_(eo)A_(es)A_(es)A_(e), wherein:

-   -   A=an adenine nucleobase,     -   mC=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE sugar moiety,     -   d=a 2′-β-D-deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 1348259 is represented by the following chemical structure:

Structure 1. Compound No. 1348259

In certain embodiments, the sodium salt of Compound No. 1348259 is represented by the following chemical structure:

Structure 2. The sodium Salt of Compound No. 1348259

2. Compound No. 1348289

In certain embodiments, Compound No. 1348289 is characterized as a 6-10-4 MOE gapmer having a sequence (from 5′ to 3′) of CACGACATATTTTTCTACAC (SEQ ID NO: 2514), wherein each of nucleosides 1-6 and 17-20 (from 5′ to 3′) are 2′-MOE nucleosides and each of nucleosides 7-16 are 2′-β-D-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, and 17 to 18 are phosphodiester internucleoside linkages, the internucleoside linkages between nucleosides 1 to 2, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 16 to 17, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments, Compound No. 1348289 is represented by the following chemical notation: mCesAeomCeoGeoAeomCeoAdsTdsAdsTdsTdsTdsTdsTdsmCdsTdsAeomCesAesmCe (SEQ ID NO: 2514), wherein:

(SEQ ID NO: 2514) ^(m)C_(es)A_(eo) ^(m)C_(eo)G_(eo)A_(eo) ^(m)C_(eo)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(eo) ^(m)C_(es)A_(es) ^(m)C_(e),

-   -   A=an adenine nucleobase,     -   ^(m)C=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE sugar moiety,     -   d=a 2′-β-D-deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 1348289 is represented by the following chemical structure:

Structure 3. Compound No. 1348289

In certain embodiments, the sodium salt of Compound No. 1348289 is represented by the following chemical structure:

Structure 4. The sodium salt of Compound No. 1348289

3. Compound No. 1348290

In certain embodiments, Compound No. 1348290 is characterized as a 6-10-4 MOE gapmer having a sequence (from 5′ to 3′) of CCACGACATATTTTTCTACA (SEQ ID NO: 2510), wherein each of nucleosides 1-6 and 17-20 (from 5′ to 3′) are 2′-MOE nucleosides and each of nucleosides 7-16 are 2′-β-D-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, and 17 to 18 are phosphodiester internucleoside linkages, the internucleoside linkages between nucleosides 1 to 2, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 16 to 17, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments, Compound No. 1348290 is represented by the following chemical notation:

(SEQ ID NO: 2510) ^(m)C_(es) ^(m)C_(eo)A_(eo) ^(m)C_(eo)G_(eo)A_(eo) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(eo)A_(es) ^(m)C_(es)A_(e), wherein:

-   -   A=an adenine nucleobase,     -   ^(m)C=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE sugar moiety,     -   d=a 2′-β-D-deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 1348290 is represented by the following chemical structure:

Structure 5: Compound No. 1348290

In certain embodiments, the sodium salt of Compound No. 1348290 is represented by the following chemical structure:

Structure 6: The Sodium Salt of Compound No. 1348290

4. Compound No. 1348331

In certain embodiments, Compound No. 1348331 is characterized as a 6-10-4 MOE gapmer having a sequence (from 5′ to 3′) of TCTGCATGTAACCTTTATAC (SEQ ID NO: 2487), wherein each of nucleosides 1-6 and 17-20 (from 5′ to 3′) are 2′-MOE nucleosides and each of nucleosides 7-16 are 2′-β-D-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, and 17 to 18 are phosphodiester internucleoside linkages, the internucleoside linkages between nucleosides 1 to 2, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 16 to 17, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments, Compound No. 1348331 is represented by the following chemical notation:

(SEQ ID NO: 2487) T_(es) ^(m)C_(eo)T_(eo)G_(eo) ^(m)C_(eo)A_(eo)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(eo)T_(es)A_(es) ^(m)C_(e), wherein:

-   -   A=an adenine nucleobase,     -   ^(m)C=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE sugar moiety,     -   d=a 2′-β-D-deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 1348331 is represented by the following chemical structure:

Structure 7: Compound No. 1348331

In certain embodiments, the sodium salt of Compound No. 1348331 is represented by the following chemical structure:

Structure 8: The Sodium Salt of Compound No. 1348331

5. Compound No. 1348347

In certain embodiments, Compound No. 1348347 is characterized as a 6-10-4 MOE gapmer having a sequence (from 5′ to 3′) of GCATAATCCCATTATACAAA (SEQ ID NO: 2493), wherein each of nucleosides 1-6 and 17-20 (from 5′ to 3′) are 2′-MOE nucleosides and each of nucleosides 7-16 are 2′-β-D-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, and 17 to 18 are phosphodiester internucleoside linkages, the internucleoside linkages between nucleosides 1 to 2, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 16 to 17, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments, Compound No. 1348347 is represented by the following chemical notation:

(SEQ ID NO: 2493) G_(es) ^(m)C_(eo)A_(eo)T_(eo)A_(eo)A_(eo)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(eo)A_(es)A_(es)A_(e), wherein:

-   -   A=an adenine nucleobase,     -   ^(m)C=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE sugar moiety,     -   d=a 2′-β-D-deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 1348347 is represented by the following chemical structure:

Structure 9: Compound No. 1348347

In certain embodiments, the sodium salt of Compound No. 1348347 is represented by the following chemical structure:

Structure 10: The Sodium Salt of Compound No. 1348347

6. Compound No. 1348937

In certain embodiments, Compound No. 1348937 is characterized as a 5-8-5 MOE gapmer having a sequence (from 5′ to 3′) of CTGCATGTAACCTTTATA (SEQ ID NO: 2534), wherein each of nucleosides 1-5 and 14-18 (from 5′ to 3′) are 2′-MOE nucleosides and each of nucleosides 6-13 are 2′-β-D-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 14 to 15 and 15 to 16 are phosphodiester internucleoside linkages, the internucleoside linkages between nucleosides 1 to 2, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 16 to 17, and 17 to 18 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments, Compound No. 1348937 is represented by the following chemical notation:

(SEQ ID NO: 2534) ^(m)C_(es)T_(eo)G_(eo) ^(m)C_(eo)A_(es)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(eo)T_(eo)A_(es)T_(es)A_(e), wherein:

-   -   A=an adenine nucleobase,     -   ^(m)C=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE sugar moiety,     -   d=a 2′-β-D-deoxyribosyl sugar moiety,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 1348937 is represented by the following chemical structure:

Structure 11: Compound No. 1348937

In certain embodiments, the sodium salt of Compound No. 1348937 is represented by the following chemical structure:

Structure 12: The Sodium Salt of Compound No. 1348937

VIII. Certain Hotspot Regions

In certain embodiments, nucleobases in the ranges specified below comprise a hotspot region of SCN2A nucleic acid. In certain embodiments, modified oligonucleotides that are complementary to an equal length portion within a hotspot region of SCN2A nucleic acid achieve an average of 69.9% or greater reduction of SCN2A RNA in vitro in the standard in vitro assay. In certain embodiments, modified oligonucleotides that are complementary to an equal length portion within a hotspot region of SCN2A nucleic acid achieve an average of 59% or greater reduction of SCN2A RNA in vivo in the standard in vivo assay.

1. Nucleobases 2306-2367 of SEQ ID NO: 1 or 199863-199905 of SEQ ID NO: 2

In certain embodiments, nucleobases 2306-2367 of SEQ ID NO: 1 or 199863-199905 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to an equal length portion within nucleobases 2306-2367 of SEQ ID NO: 1 or 199863-199905 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are 18 nucleobases in length. In certain embodiments, modified oligonucleotides are 16, 17, 18, 19, 20, 21, or 22 nucleobases in length. In certain embodiments, modified oligonucleotides consist of 17-19 or 21-30 linked nucleosides. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the gapmers are 6-10-4 MOE gapmers. In certain embodiments, the gapmers are 4-10-6 MOE gapmers. In certain embodiments, the gapmers are 4-8-6 MOE gapmers. In certain embodiments, the gapmers are 6-8-4 MOE gapmers. In certain embodiments, the gapmers are 5-8-5 MOE gapmers. In certain embodiments, the gapmers have the sugar motif in order from 5′ to 3′: eeeeeddddddddddeeeee, eeeeeeddddddddddeeee, eeeeddddddddddeeeeee, eeeeddddddddeeeeee, eeeeeeddddddddeeee, or eeeeeddddddddeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. In certain embodiments, the gapmers comprise a 2′-substituted nucleoside in the gap. In certain embodiments, the 2′-substituted nucleoside comprises a 2′-OMe sugar moiety. In certain embodiments, the 2′-substituted nucleoside is at position 2 of the gap (5′ to 3′).

In certain embodiments, modified oligonucleotides do not comprise a bicyclic sugar moiety. In certain embodiments, modified oligonucleotides do not comprise more than one, two, three, four, five, six, seven, eight, or nine bicyclic sugar moieties. In certain embodiments, modified oligonucleotides comprise one or two wing segments that comprise a nucleoside that is not a bicyclic nucleoside. In certain embodiments, modified oligonucleotides do not comprise a LNA sugar moiety. In certain embodiments, modified oligonucleotides do not comprise more than one, two, three, four, five, six, seven, eight, or nine LNA sugar moieties. In certain embodiments, modified oligonucleotides comprise one or two wing segments that comprise a nucleoside that is not a LNA nucleoside.

In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′. In certain embodiments, the modified nucleotides have an internucleoside linkage motif of (from 5′ to 3′) of soooossssssssssooss, sooooossssssssssoss, sooossssssssssoooss, soosssssssssoooss, soooosssssssssoss, or sooosssssssssooss wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

The nucleobase sequences of SEQ ID NOs: 336, 488, 2021, 2097, 2174, 2250, 2326, 2403, 2499, 2500, 2501, 2502, and 2526 are complementary to an equal length portion within nucleobases 2306-2367 of SEQ ID NO: 1 or 199863-199905 of SEQ ID NO: 2.

The nucleobase sequence of Compound IDs: 909979, 1248427, 1248428, 1248429, 1248430, 1248431, 1248432, 1248433, 1348279, 1348282, 1348286, 1348297, 1348328, 1348343, 1348358, 1348360, 1348361, 1348362, 1348364, 1348365, 1348366, 1348367, 1348378, and 1348380 are complementary to an equal length portion within nucleobases 2306-2367 of SEQ ID NO: 1 or 199863-199905 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 2306-2367 of SEQ ID NO: 1 or 199863-199905 of SEQ ID NO: 2 achieve at least 53% reduction of SCN2A RNA in vitro in the standard in vitro assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 2306-2367 of SEQ ID NO: 1 or 199863-199905 of SEQ ID NO: 2 achieve an average of 69.9% reduction of SCN2A RNA in vitro in the standard in vitro assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 2306-2367 of SEQ ID NO: 1 or 199863-199905 of SEQ ID NO: 2 achieve an average of 77.1% reduction of SCN2A RNA in vivo in the standard in vivo assay.

In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 2306-2367 of SEQ ID NO: 1 or 199863-199905 of SEQ ID NO: 2 achieve an average of 63.2% reduction of SCN2A RNA in vivo in the standard in vivo assay.

2. Nucleobases 3499-3557 of SEQ ID NO: 1 or 227493-227551 of SEQ ID NO: 2

In certain embodiments, nucleobases 3499-3557 of SEQ ID NO: 1 or 227493-227551 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to an equal length portion within nucleobases 3499-3557 of SEQ ID NO: 1 or 227493-227551 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are 18 nucleobases in length. In certain embodiments, modified oligonucleotides are 16, 17, 18, 19, 20, 21, or 22 nucleobases in length. In certain embodiments, modified oligonucleotides consist of 17-19 or 21-30 linked nucleosides. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the gapmers are 6-10-4 MOE gapmers. In certain embodiments, the gapmers are 4-10-6 MOE gapmers. In certain embodiments, the gapmers are 4-8-6 MOE gapmers. In certain embodiments, the gapmers are 6-8-4 MOE gapmers. In certain embodiments, the gapmers are 5-8-5 MOE gapmers. In certain embodiments, the gapmers have the sugar motif in order from 5′ to 3′: eeeeeddddddddddeeeee, eeeeeeddddddddddeeee, eeeeddddddddddeeeeee, eeeeddddddddeeeeee, eeeeeeddddddddeeee, or eeeeeddddddddeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. In certain embodiments, the gapmers comprise a 2′-substituted nucleoside in the gap. In certain embodiments, the 2′-substituted nucleoside comprises a 2′-OMe sugar moiety. In certain embodiments, the 2′-substituted nucleoside is at position 2 of the gap (5′ to 3′).

In certain embodiments, modified oligonucleotides do not comprise a bicyclic sugar moiety. In certain embodiments, modified oligonucleotides do not comprise more than one, two, three, four, five, six, seven, eight, or nine bicyclic sugar moieties. In certain embodiments, modified oligonucleotides comprise one or two wing segments that comprise a nucleoside that is not a bicyclic nucleoside. In certain embodiments, modified oligonucleotides do not comprise a LNA sugar moiety. In certain embodiments, modified oligonucleotides do not comprise more than one, two, three, four, five, six, seven, eight, or nine LNA sugar moieties. In certain embodiments, modified oligonucleotides comprise one or two wing segments that comprise a nucleoside that is not a LNA nucleoside.

In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′. In certain embodiments, the modified nucleotides have an internucleoside linkage motif of (from 5′ to 3′) of soooossssssssssooss, sooooossssssssssoss, sooossssssssssoooss, soosssssssssoooss, soooosssssssssoss, or sooosssssssssooss wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

The nucleobase sequences of SEQ ID NOs: 181, 259, 643, 720, 796, 2504, 2505, 2506, 2507, 2508, 2509, 2510, 2511, 2512, 2513, 2514, and 2521 are complementary to an equal length portion within nucleobases 3499-3557 of SEQ ID NO: 1 or 227493-227551 of SEQ ID NO: 2.

The nucleobase sequence of Compound IDs: 909989, 909990, 1248487, 1248488, 1248489, 1348289, 1348290, 1348291, 1348292, 1348295, 1348298, 1348302, 1348303, 1348304, 1348306, 1348307, 1348369, 1348370, 1348371, 1348373, 1348374, 1348375, 1348376, 1348377, 1348381, 1348382, 1348383, 1348384, 1348385, 1348386, 1348387, 1348405, 1348411, 1348423, 1348439, 1348440, 1348441, 1348442, 1348443, 1348444, 1348446, 1348447, and 1348456 are complementary to an equal length portion within nucleobases 3499-3557 of SEQ ID NO: 1 or 227493-227551 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 3499-3557 of SEQ ID NO: 1 or 227493-227551 of SEQ ID NO: 2 achieve at least 75% reduction of SCN2A RNA in vitro in the standard in vitro assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 3499-3557 of SEQ ID NO: 1 or 227493-227551 of SEQ ID NO: 2 achieve an average of 81.6% reduction of SCN2A RNA in vitro in the standard in vitro assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 3499-3557 of SEQ ID NO: 1 or 227493-227551 of SEQ ID NO: 2 achieve an average of 76.6% reduction of SCN2A RNA in vivo in the standard in vivo assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 3499-3557 of SEQ ID NO: 1 or 227493-227551 of SEQ ID NO: 2 achieve an average of 67.2% reduction of SCN2A RNA in vivo in the standard in vivo assay.

3. Nucleobases 243124-243204 of SEQ ID NO: 2

In certain embodiments, nucleobases 243124-243204 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to an equal length portion within nucleobases 243124-243204 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are 18 nucleobases in length. In certain embodiments, modified oligonucleotides are 16, 17, 18, 19, 20, 21, or 22 nucleobases in length. In certain embodiments, modified oligonucleotides consist of 17-19 or 21-30 linked nucleosides. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the gapmers are 6-10-4 MOE gapmers. In certain embodiments, the gapmers are 4-10-6 MOE gapmers. In certain embodiments, the gapmers are 4-8-6 MOE gapmers. In certain embodiments, the gapmers are 6-8-4 MOE gapmers. In certain embodiments, the gapmers are 5-8-5 MOE gapmers. In certain embodiments, the gapmers have the sugar motif in order from 5′ to 3′: eeeeeddddddddddeeeee, eeeeeeddddddddddeeee, eeeeddddddddddeeeeee, eeeeddddddddeeeeee, eeeeeeddddddddeeee, or eeeeeddddddddeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. In certain embodiments, the gapmers comprise a 2′-substituted nucleoside in the gap. In certain embodiments, the 2′-substituted nucleoside comprises a 2′-OMe sugar moiety. In certain embodiments, the 2′-substituted nucleoside is at position 2 of the gap (5′ to 3′).

In certain embodiments, modified oligonucleotides do not comprise a bicyclic sugar moiety. In certain embodiments, modified oligonucleotides do not comprise more than one, two, three, four, five, six, seven, eight, or nine bicyclic sugar moieties. In certain embodiments, modified oligonucleotides comprise one or two wing segments that comprise a nucleoside that is not a bicyclic nucleoside. In certain embodiments, modified oligonucleotides do not comprise a LNA sugar moiety. In certain embodiments, modified oligonucleotides do not comprise more than one, two, three, four, five, six, seven, eight, or nine LNA sugar moieties. In certain embodiments, modified oligonucleotides comprise one or two wing segments that comprise a nucleoside that is not a LNA nucleoside.

In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′. In certain embodiments, the modified nucleotides have an internucleoside linkage motif of (from 5′ to 3′) of soooossssssssssooss, sooooossssssssssoss, sooossssssssssoooss, soosssssssssoooss, soooosssssssssoss, or sooosssssssssooss wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

The nucleobase sequences of SEQ ID NOs: 491, 567, 644, 721, 797, 2177, 2253, 2315, 2329, 2406, and 2527 are complementary to an equal length portion within nucleobases 243124-243204 of SEQ ID NO: 2.

The nucleobase sequence of Compound IDs: 1248507, 1248508, 1248509, 1248510, 1248511, 1248512, 1248513, 1248514, 1248515, 1250138, 1348299, 1348379, 1348388, and 1348397 are complementary to an equal length portion within nucleobases 243124-243204 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 243124-243204 of SEQ ID NO: 2 achieve at least 51% reduction of SCN2A RNA in vitro in the standard in vitro assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 243124-243204 of SEQ ID NO: 2 achieve an average of 71.4% reduction of SCN2A RNA in vitro in the standard in vitro assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 243124-243204 of SEQ ID NO: 2 achieve an average of 61.3% reduction of SCN2A RNA in vivo in the standard in vivo assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 243124-243204 of SEQ ID NO: 2 achieve an average of 61.5% reduction of SCN2A RNA in vivo in the standard in vivo assay.

4. Nucleobases 243917-244073 of SEQ ID NO: 2

In certain embodiments, nucleobases 243917-244073 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to an equal length portion within nucleobases 243917-244073 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are 18 nucleobases in length. In certain embodiments, modified oligonucleotides are 16, 17, 18, 19, 20, 21, or 22 nucleobases in length. In certain embodiments, modified oligonucleotides consist of 17-19 or 21-30 linked nucleosides. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the gapmers are 6-10-4 MOE gapmers. In certain embodiments, the gapmers are 4-10-6 MOE gapmers. In certain embodiments, the gapmers are 4-8-6 MOE gapmers. In certain embodiments, the gapmers are 6-8-4 MOE gapmers. In certain embodiments, the gapmers are 5-8-5 MOE gapmers. In certain embodiments, the gapmers have the sugar motif in order from 5′ to 3′: eeeeeddddddddddeeeee, eeeeeeddddddddddeeee, eeeeddddddddddeeeeee, eeeeddddddddeeeeee, eeeeeeddddddddeeee, or eeeeeddddddddeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. In certain embodiments, the gapmers comprise a 2′-substituted nucleoside in the gap. In certain embodiments, the 2′-substituted nucleoside comprises a 2′-OMe sugar moiety. In certain embodiments, the 2′-substituted nucleoside is at position 2 of the gap (5′ to 3′).

In certain embodiments, modified oligonucleotides do not comprise a bicyclic sugar moiety. In certain embodiments, modified oligonucleotides do not comprise more than one, two, three, four, five, six, seven, eight, or nine bicyclic sugar moieties. In certain embodiments, modified oligonucleotides comprise one or two wing segments that comprise a nucleoside that is not a bicyclic nucleoside. In certain embodiments, modified oligonucleotides do not comprise a LNA sugar moiety. In certain embodiments, modified oligonucleotides do not comprise more than one, two, three, four, five, six, seven, eight, or nine LNA sugar moieties. In certain embodiments, modified oligonucleotides comprise one or two wing segments that comprise a nucleoside that is not a LNA nucleoside.

In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′. In certain embodiments, the modified nucleotides have an internucleoside linkage motif of (from 5′ to 3′) of soooossssssssssooss, sooooossssssssssoss, sooossssssssssoooss, soosssssssssoooss, soooosssssssssoss, or sooosssssssssooss wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

The nucleobase sequences of SEQ ID NOs: 1090, 1166, 2484, 2485, 2487, 2493, 2496, 2497, 2498, 2533, 2534, 2535, and 2537 are complementary to an equal length portion within nucleobases 243917-244073 of SEQ ID NO: 2.

The nucleobase sequence of Compound IDs: 1250148, 1250149, 1348250, 1348251, 1348253, 1348259, 1348265, 1348266, 1348267, 1348331, 1348332, 1348333, 1348338, 1348342, 1348344, 1348345, 1348347, 1348419, 1348420, 1348421, 1348427, 1348428, 1348435, 1348436, 1348437, 1348920, 1348922, 1348923, 1348925, 1348927, 1348928, 1348929, 1348931, 1348934, 1348935, 1348937, and 1348938 are complementary to an equal length portion within nucleobases 243917-244073 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 243917-244073 of SEQ ID NO: 2 achieve at least 80% reduction of SCN2A RNA in vitro in the standard in vitro assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 243917-244073 of SEQ ID NO: 2 achieve an average of 80.5% reduction of SCN2A RNA in vitro in the standard in vitro assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 243917-244073 of SEQ ID NO: 2 achieve an average of 67.7% reduction of SCN2A RNA in vivo in the standard in vivo assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 243917-244073 of SEQ ID NO: 2 achieve an average of 62.1% reduction of SCN2A RNA in vivo in the standard in vivo assay.

5. Nucleobases 4389-4487 of SEQ ID NO: 1 or 247823-247921 of SEQ ID NO: 2

In certain embodiments, nucleobases 4389-4487 of SEQ ID NO: 1 or 247823-247921 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to an equal length portion within nucleobases 4389-4487 of SEQ ID NO: 1 or 247823-247921 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are 18 nucleobases in length. In certain embodiments, modified oligonucleotides are 16, 17, 18, 19, 20, 21, or 22 nucleobases in length. In certain embodiments, modified oligonucleotides consist of 17-19 or 21-30 linked nucleosides. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the gapmers are 6-10-4 MOE gapmers. In certain embodiments, the gapmers are 4-10-6 MOE gapmers. In certain embodiments, the gapmers are 4-8-6 MOE gapmers. In certain embodiments, the gapmers are 6-8-4 MOE gapmers. In certain embodiments, the gapmers are 5-8-5 MOE gapmers. In certain embodiments, the gapmers have the sugar motif in order from 5′ to 3′: eeeeeddddddddddeeeee, eeeeeeddddddddddeeee, eeeeddddddddddeeeeee, eeeeddddddddeeeeee, eeeeeeddddddddeeee, or eeeeeddddddddeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. In certain embodiments, the gapmers comprise a 2′-substituted nucleoside in the gap. In certain embodiments, the 2′-substituted nucleoside comprises a 2′-OMe sugar moiety. In certain embodiments, the 2′-substituted nucleoside is at position 2 of the gap (5′ to 3′).

In certain embodiments, modified oligonucleotides do not comprise a bicyclic sugar moiety. In certain embodiments, modified oligonucleotides do not comprise more than one, two, three, four, five, six, seven, eight, or nine bicyclic sugar moieties. In certain embodiments, modified oligonucleotides comprise one or two wing segments that comprise a nucleoside that is not a bicyclic nucleoside. In certain embodiments, modified oligonucleotides do not comprise a LNA sugar moiety. In certain embodiments, modified oligonucleotides do not comprise more than one, two, three, four, five, six, seven, eight, or nine LNA sugar moieties. In certain embodiments, modified oligonucleotides comprise one or two wing segments that comprise a nucleoside that is not a LNA nucleoside.

In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′. In certain embodiments, the modified nucleotides have an internucleoside linkage motif of (from 5′ to 3′) of soooossssssssssooss, sooooossssssssssoss, sooossssssssssoooss, soosssssssssoooss, soooosssssssssoss, or sooosssssssssooss wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

The nucleobase sequences of SEQ ID NOs: 29, 30, 107, 108, 185, 186, 263, 264, 341, 342, 419, 420, 1796, 1871, 1948, 2025, 2101, 2178, 2254, 2330, 2503, 2517, and 2522 are complementary to an equal length portion within nucleobases 4389-4487 of SEQ ID NO: 1 or 247823-247921 of SEQ ID NO: 2.

The nucleobase sequence of Compound IDs: 910009, 910010, 910011, 910012, 910013, 910014, 910015, 910016, 910017, 910018, 910019, 910020, 1248528, 1248529, 1248530, 1248531, 1248532, 1248533, 1248534, 1248535, 1348269, 1348270, 1348271, 1348275, 1348277, 1348348, 1348353, 1348355, 1348356, 1348396, and 1348450 are complementary to an equal length portion within nucleobases 4389-4487 of SEQ ID NO: 1 or 247823-247921 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 4389-4487 of SEQ ID NO: 1 or 247823-247921 of SEQ ID NO: 2 achieve at least 27% reduction of SCN2A RNA in vitro in the standard in vitro assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 4389-4487 of SEQ ID NO: 1 or 247823-247921 of SEQ ID NO: 2 achieve an average of 71.1% reduction of SCN2A RNA in vitro in the standard in vitro assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 4389-4487 of SEQ ID NO: 1 or 247823-247921 of SEQ ID NO: 2 achieve an average of 63.4% reduction of SCN2A RNA in vivo in the standard in vivo assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 4389-4487 of SEQ ID NO: 1 or 247823-247921 of SEQ ID NO: 2 achieve an average of 59.1% reduction of SCN2A RNA in vivo in the standard in vivo assay.

6. Nucleobases 4774-4809 of SEQ ID NO: 1 or 254142-254177 of SEQ ID NO: 2

In certain embodiments, nucleobases 4774-4809 of SEQ ID NO: 1 or 254142-254177 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to an equal length portion within nucleobases 4774-4809 of SEQ ID NO: 1 or 254142-254177 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are 18 nucleobases in length. In certain embodiments, modified oligonucleotides are 16, 17, 18, 19, 20, 21, or 22 nucleobases in length. In certain embodiments, modified oligonucleotides consist of 17-19 or 21-30 linked nucleosides. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the gapmers are 6-10-4 MOE gapmers. In certain embodiments, the gapmers are 4-10-6 MOE gapmers. In certain embodiments, the gapmers are 4-8-6 MOE gapmers. In certain embodiments, the gapmers are 6-8-4 MOE gapmers. In certain embodiments, the gapmers are 5-8-5 MOE gapmers. In certain embodiments, the gapmers have the sugar motif in order from 5′ to 3′: eeeeeddddddddddeeeee, eeeeeeddddddddddeeee, eeeeddddddddddeeeeee, eeeeddddddddeeeeee, eeeeeeddddddddeeee, or eeeeeddddddddeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. In certain embodiments, the gapmers comprise a 2′-substituted nucleoside in the gap. In certain embodiments, the 2′-substituted nucleoside comprises a 2′-OMe sugar moiety. In certain embodiments, the 2′-substituted nucleoside is at position 2 of the gap (5′ to 3′).

In certain embodiments, modified oligonucleotides do not comprise a bicyclic sugar moiety. In certain embodiments, modified oligonucleotides do not comprise more than one, two, three, four, five, six, seven, eight, or nine bicyclic sugar moieties. In certain embodiments, modified oligonucleotides comprise one or two wing segments that comprise a nucleoside that is not a bicyclic nucleoside. In certain embodiments, modified oligonucleotides do not comprise a LNA sugar moiety. In certain embodiments, modified oligonucleotides do not comprise more than one, two, three, four, five, six, seven, eight, or nine LNA sugar moieties. In certain embodiments, modified oligonucleotides comprise one or two wing segments that comprise a nucleoside that is not a LNA nucleoside.

In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′. In certain embodiments, the modified nucleotides have an internucleoside linkage motif of (from 5′ to 3′) of soooossssssssssooss, sooooossssssssssoss, sooossssssssssoooss, soosssssssssoooss, soooosssssssssoss, or sooosssssssssooss wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

The nucleobase sequences of SEQ ID NOs: 1016, 1093, 1104, 1169, 1246, 1323, 1400, 1477, 1554, 1708, 1785, 1860, 1937, 2014, 1631, 2090, and 2539 are complementary to an equal length portion within nucleobases 4774-4809 of SEQ ID NO: 1 or 254142-254177 of SEQ ID NO: 2.

The nucleobase sequence of Compound IDs: 1248544, 1250225, 1250226, 1250227, 1250228, 1250229, 1250230, 1250231, 1250232, 1250233, 1250234, 1250235, 1250236, 1250237, 1250238, 1250239, 1348936, and 1348939 are complementary to an equal length portion within nucleobases 4774-4809 of SEQ ID NO: 1 or 254142-254177 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 4774-4809 of SEQ ID NO: 1 or 254142-254177 of SEQ ID NO: 2 achieve at least 51% reduction of SCN2A RNA in vitro in the standard in vitro assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 4774-4809 of SEQ ID NO: 1 or 254142-254177 of SEQ ID NO: 2 achieve an average of 89% reduction of SCN2A RNA in vitro in the standard in vitro assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 4774-4809 of SEQ ID NO: 1 or 254142-254177 of SEQ ID NO: 2 achieve an average of 74.8% reduction of SCN2A RNA in vivo in the standard in vivo assay. In certain embodiments, modified oligonucleotides complementary to an equal length portion within nucleobases 4774-4809 of SEQ ID NO: 1 or 254142-254177 of SEQ ID NO: 2 achieve an average of 67.8% reduction of SCN2A RNA in vivo in the standard in vivo assay.

7. Additional Hotspot Regions

In certain embodiments, the ranges described in the table below comprise hotspot regions. Each hotspot region begins with the nucleobase of SEQ ID NO:2 identified in the “Start Site SEQ ID NO: 2” column and ends with the nucleobase of SEQ ID NO: 2 identified in the “Stop Site SEQ ID NO: 2” column. In certain embodiments, modified oligonucleotides are complementary to an equal length portion within any of the hotspot regions 1-17, as defined in the table below. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are 18 nucleobases in length. In certain embodiments, modified oligonucleotides are 16, 17, 18, 19, 20, 21, or 22 nucleobases in length. In certain embodiments, modified oligonucleotides consist of 17-19 or 21-30 linked nucleosides. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the gapmers are 6-10-4 MOE gapmers. In certain embodiments, the gapmers are 4-10-6 MOE gapmers. In certain embodiments, the gapmers are 4-8-6 MOE gapmers. In certain embodiments, the gapmers are 6-8-4 MOE gapmers. In certain embodiments, the gapmers are 5-8-5 MOE gapmers. In certain embodiments, the gapmers have the sugar motif in order from 5′ to 3′: eeeeeddddddddddeeeee, eeeeeeddddddddddeeee, eeeeddddddddddeeeeee, eeeeddddddddeeeeee, eeeeeeddddddddeeee, or eeeeeddddddddeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. In certain embodiments, the gapmers comprise a 2′-substituted nucleoside in the gap. In certain embodiments, the 2′-substituted nucleoside comprises a 2′-OMe sugar moiety. In certain embodiments, the 2′-substituted nucleoside is at position 2 of the gap (5′ to 3′).

In certain embodiments, modified oligonucleotides do not comprise a bicyclic sugar moiety. In certain embodiments, modified oligonucleotides do not comprise more than one, two, three, four, five, six, seven, eight, or nine bicyclic sugar moieties. In certain embodiments, modified oligonucleotides comprise one or two wing segments that comprise a nucleoside that is not a bicyclic nucleoside. In certain embodiments, modified oligonucleotides do not comprise a LNA sugar moiety. In certain embodiments, modified oligonucleotides do not comprise more than one, two, three, four, five, six, seven, eight, or nine LNA sugar moieties. In certain embodiments, modified oligonucleotides comprise one or two wing segments that comprise a nucleoside that is not a LNA nucleoside.

In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′. In certain embodiments, the modified nucleotides have an internucleoside linkage motif of (from 5′ to 3′) of soooossssssssssooss, sooooossssssssssoss, sooossssssssssoooss, soosssssssssoooss, soooosssssssssoss, or sooosssssssssooss wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

The nucleobase sequence of compounds listed in the “Compound IDs in range” column in the table below are complementary to SEQ ID NO: 2 within the specified hotspot region. The nucleobase sequence of the oligonucleotides listed in the “SEQ ID NOs in range” column in the table below are complementary to the target sequence, SEQ ID NO: 2, within the specified hotspot region.

In certain embodiments, modified oligonucleotides complementary to nucleobases within the hotspot region achieve at least “Min.% Red. in vitro” (minimum % reduction, relative to untreated control cells) of SCN2A RNA in vitro in the standard in vitro assay, as indicated in the table below. In certain embodiments, modified oligonucleotides complementary to nucleobases within the hotspot region achieve an average of “Avg.% Red. in vitro” (average % reduction, relative to untreated control cells) of SCN2A RNA in vitro in the standard in vitro assay, as indicated in the table below. In certain embodiments, modified oligonucleotides complementary to nucleobases within the hotspot region achieve a maximum of “Max. % Red. in vitro” (maximum % reduction, relative to untreated control cells) of SCN2A RNA in vitro in the standard in vitro assay, as indicated in the table below. In certain embodiments, modified oligonucleotides complementary to nucleobases within the hotspot region achieve an average of “Avg. % Red. in vivo Cortex” (average % reduction, relative to PBS-treated animals) of SCN2A RNA in vivo in the standard in vivo assay in cortical tissue, as indicated in the table below. In certain embodiments, modified oligonucleotides complementary to nucleobases within the hotspot region achieve an average of “Avg. % Red. in vivo Spinal” (average % reduction, relative to PBS-treated animals) of SCN2A RNA in vivo in the standard in vivo assay in spinal cord tissue, as indicated in the table below. “n.d.” indicates that no in vivo data is available for compounds within that range. In other cases, average reduction in vivo includes a subset of the compounds in any given hotspot, as not all compounds were tested in vivo.

TABLE 1 SCN2A Hotspots Avg % Avg % Start Site Stop Site Min % Max % Avg % Red. in Red. in SEQ ID Hotspot SEQ ID SEQ ID Red. in Red. in Red. in vivo vivo Compound IDs NOs in ID NO: 2 NO: 2 vitro vitro vitro Cortex Spinal in range range 1 199863 199905 53 83 69.9 77.1 63.2 909979, 1248427, 336, 488, 1248428, 1248429, 2021, 1248430, 1248431, 2097, 1248432, 1248433, 2174, 1348279, 1348282, 2250, 1348286, 1348297, 2326, 1348328, 1348343, 2403, 1348358, 1348360, 2499, 1348361, 1348362, 2500, 1348364, 1348365, 2501, 1348366, 1348367, 2502, and 1348378, and 2526 1348380 2 227493 227551 75 88 81.6 76.6 67.2 909989, 909990, 181, 259, 1248487, 1248488, 643, 720, 1248489, 1348289, 796, 2504, 1348290, 1348291, 2505, 1348292, 1348295, 2506, 1348298, 1348302, 2507, 1348303, 1348304, 2508, 1348306, 1348307, 2509, 1348369, 1348370, 2510, 1348371, 1348373, 2511, 1348374, 1348375, 2512, 1348376, 1348377, 2513, 1348381, 1348382, 2514, and 1348383, 1348384, 2521 1348385, 1348386, 1348387, 1348405, 1348411, 1348423, 1348439, 1348440, 1348441, 1348442, 1348443, 1348444, 1348446, 1348447, and 1348456 3 243124 243204 51 90 71.4 61.3 61.5 1248507, 1248508, 491, 567, 1248509, 1248510, 644, 721, 1248511, 1248512, 797, 2177, 1248513, 1248514, 2253, 1248515, 1250138, 2315, 1348299, 1348379, 2329, 1348388, and 2406, and 1348397 2527 4 243917 244073 80 81 80.5 67.7 62.1 1250148, 1250149, 1090, 1348250, 1348251, 1166, 1348253, 1348259, 2484, 1348265, 1348266, 2485, 1348267, 1348331, 2487, 1348332, 1348333, 2493, 1348338, 1348342, 2496, 1348344, 1348345, 2497, 1348347, 1348419, 2498, 1348420, 1348421, 2533, 1348427, 1348428, 2534, 1348435, 1348436, 2535, and 1348437, 1348920, 2537 1348922, 1348923, 1348925, 1348927, 1348928, 1348929, 1348931, 1348934, 1348935, 1348937, and 1348938 5 247823 247921 27 92 71.1 63.4 59.1 910009, 910010, 29, 30, 910011, 910012, 107, 108, 910013, 910014, 185, 186, 910015, 910016, 263, 264, 910017, 910018, 341, 342, 910019, 910020, 419, 420, 1248528, 1248529, 1796, 1248530, 1248531, 1871, 1248532, 1248533, 1948, 1248534, 1248535, 2025, 1348269, 1348270, 2101, 1348271, 1348275, 2178, 1348277, 1348348, 2254, 1348353, 1348355, 2330, 1348356, 1348396, 2503, and 1348450 2517, and 2522 6 254142 254177 51 89 71.7 74.8 67.8 1248544, 1250225, 1016, 1250226, 1250227, 1093, 1250228, 1250229, 1104, 1250230, 1250231, 1169, 1250232, 1250233, 1246, 1250234, 1250235, 1323, 1250236, 1250237, 1400, 1250238, 1250239, 1477, 1348936, and 1554, 1348939 1708, 1785, 1860, 1937, 2014, 1631, 2090, and 2539 7 168911 168945 71 93 81.2 n.d. n.d. 909945, 909946, 18, 96, 1248352, 1248353, 485, 561, 1248354, 1248355, 638, 715, 1248356, 1248357, 791, 868, 1248358, 1248359, 2247, and 1248360. 2323, and 2400 8 170026 170061 65 84 82.3 n.d. n.d. 909947, 1248366, 174, 1328, 1248367, 1248368, 1405, 1248369, 1248370, 1482, 1248371, 1248372, 1559, 1248373, 1248374, 1636, and 1248375 1713, 1790, 1865, 1942, and 2019 9 170174 170200 69 93 81.6 n.d. n.d. 910246, 1249167, 302, 1513, 1249168, 1249169, 1667, 1249170, 1249171, 1744, and 1249172 1819, 1896, and 1973 10 176724 176751 75 94 86.7 n.d. n.d. 910256, 910257, 148, 226, 1249294, 1249295, 1364, 1249296, 1249297, 1441, 1249298, and 1518, 1249299 1595, 1672, and 1749 11 180772 180801 67 93 78.6 n.d. n.d. 910263, 1249423, 227, 1292, 1249424, 1249425, 1369. 1249426, 1249427, 1446, 1249428, 1249429, 1523, and 1249430 1600, 1677, 1754, and 1829 12 183519 183562 73 97 83.1 n.d. n.d. 909954, 909955, 20, 98, 909956, 909957, 253, 332, 909958, 1248393, 410, 1406, 1248394, 1248395, 1483, 1248396, 1248397, 1560, 1248398, 1248399, 1637, and 1248400 1714, 1791, 1866, and 1943 13 183968 184016 60 95 77.1 n.d. n.d. 910269, 1249480, 228, 1679, 1249481, 1249482, 1756, 1249483, 1249484, 1831, 1249485, 1249486, 1908, 1249487, and 1985, 1249488 2061, 2138, 2214, and 2290 14 188630 188668 68 86 77.1 n.d. n.d. 909962, 909963, 21, 411, 1248419, 1248420, 1407, 1248421, 1248422, 1484, and 1248423 1561, 1638, and 1715 15 199912 199962 72 94 82.7 n.d. n.d. 909980, 909981, 24, 414, 1248438, 1248439, 871, 948, 1248440, and 1025, and 1248441 1100 16 202877 202906 70 92 81.5 n.d. n.d. 1249708, 1249709, 1226, 1249710, 1249711, 1303, 1249712, and 1380, 1249713 1457, 1534, and 1611 17 227419 227450 67 92 80.6 n.d. n.d. 909985, 909986, 25, 337, 909987, 1248480, 415, 490, 1248481, 1248482, 566, 2099, 1248483, 1248484, 2176, 1248485, and 2252, 1248486 2328, and 2405

IX. Certain Comparator Compounds

Comparator Compound No. 1506060 was selected as a comparator compound in the experiment described in Example 4 of the instant specification. Comparator Compound No. 1506060, previously described in WO2020/041348, incorporated herein by reference, is a 4-8-4 LNA gapmer with the sequence (from 5′ to 3′) TGGGTCTCTTAGCTTT (SEQ ID NO: 2540), wherein the central gap segment consists of eight 2′-β-D-deoxynucleosides, the 5′ and 3′ wing segments each consist of four LNA modified nucleosides, and each internucleoside linkage is a phosphorothioate internucleoside linkage.

In certain embodiments, compounds described herein are more tolerable relative to Comparator Compound No. 1506060.

For example, as described herein (see Example 4), Comparator Compound No. 1506060 had a 3-hour FOB of 6.00 in mice, whereas Compound Nos. 1348290, 1348331, and 1348347 each had a 3-hour FOB of 0.00 in mice, and Compound Nos. 1348259, 1348289, and 1348937 each had a 3-hour FOB of 0 or 1.00 in mice. Therefore, certain compounds described herein are more tolerable than Comparator Compound No. 1506060 in this assay.

Nonlimiting Disclosure and Incorporation by Reference

Each of the literature and patent publications listed herein is incorporated by reference in its entirety.

While certain compounds, compositions and methods described herein have been described with specificity in accordance with certain embodiments, the following examples serve only to illustrate the compounds described herein and are not intended to limit the same. Each of the references, GenBank accession numbers, and the like recited in the present application is incorporated herein by reference in its entirety.

Although the sequence listing accompanying this filing identifies each sequence as either “RNA” or “DNA” as required, in reality, those sequences may be modified with any combination of chemical modifications. One of skill in the art will readily appreciate that such designation as “RNA” or “DNA” to describe modified oligonucleotides is, in certain instances, arbitrary. For example, an oligonucleotide comprising a nucleoside comprising a 2′-OH sugar moiety and a thymine base could be described as a DNA having a modified sugar (2′-OH in place of one 2′-H of DNA) or as an RNA having a modified base (thymine (methylated uracil) in place of a uracil of RNA). Accordingly, nucleic acid sequences provided herein, including, but not limited to those in the sequence listing, are intended to encompass nucleic acids containing any combination of natural or modified RNA and/or DNA, including, but not limited to such nucleic acids having modified nucleobases. By way of further example and without limitation, an oligomeric compound having the nucleobase sequence “ATCGATCG” encompasses any oligomeric compounds having such nucleobase sequence, whether modified or unmodified, including, but not limited to, such compounds comprising RNA bases, such as those having sequence “AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” and oligomeric compounds having other modified nucleobases, such as “AT^(m)CGAUCG,” wherein ^(m)C indicates a cytosine base comprising a methyl group at the 5-position.

Certain compounds described herein (e.g., modified oligonucleotides) have one or more asymmetric center and thus give rise to enantiomers, diastereomers, and other stereoisomeric configurations that may be defined, in terms of absolute stereochemistry, as (R) or (S), as a or β such as for sugar anomers, or as (D) or (L), such as for amino acids, etc. Compounds provided herein that are drawn or described as having certain stereoisomeric configurations include only the indicated compounds. Compounds provided herein that are drawn or described with undefined stereochemistry include all such possible isomers, including their stereorandom and optically pure forms, unless specified otherwise. Likewise, all cis- and trans-isomers and tautomeric forms of the compounds herein are also included unless otherwise indicated. Oligomeric compounds described herein include chirally pure or enriched mixtures as well as racemic mixtures. For example, oligomeric compounds having a plurality of phosphorothioate internucleoside linkages include such compounds in which chirality of the phosphorothioate internucleoside linkages is controlled or is random. Unless otherwise indicated, compounds described herein are intended to include corresponding salt forms.

The compounds described herein include variations in which one or more atoms are replaced with a non-radioactive isotope or radioactive isotope of the indicated element. For example, compounds herein that comprise hydrogen atoms encompass all possible deuterium substitutions for each of the ¹H hydrogen atoms. Isotopic substitutions encompassed by the compounds herein include but are not limited to: ²H or 3H in place of ¹H, ¹³C or ¹⁴C in place of ¹²C, ¹⁵N in place of ¹⁴N, ¹⁷O or ¹⁸O in place of ¹⁶O and ³³S, ³⁴S, ³⁵S, or ³⁶S in place of ³²S. In certain embodiments, non-radioactive isotopic substitutions may impart new properties on the oligomeric compound that are beneficial for use as a therapeutic or research tool. In certain embodiments, radioactive isotopic substitutions may make the compound suitable for research or diagnostic purposes such as imaging.

EXAMPLES

The following examples illustrate certain embodiments of the present disclosure and are not limiting. Moreover, where specific embodiments are provided, the inventors have contemplated generic application of those specific embodiments. For example, disclosure of an oligonucleotide having a particular motif provides reasonable support for additional oligonucleotides having the same or similar motif. And, for example, where a particular high-affinity modification appears at a particular position, other high-affinity modifications at the same position are considered suitable, unless otherwise indicated.

Example 1: Effect of 5-10-5 MOE Gapmer Modified Oligonucleotides on Human SCN2A RNA In Vitro, Single Dose

Modified Oligonucleotides Complementary to Human SCN2A Nucleic Acid were Designed and Tested for their single dose effects on SCN2A RNA in vitro. The modified oligonucleotides were tested in a series of experiments that had similar culture conditions.

The modified oligonucleotides in the tables below are 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages. The gapmers are 20 nucleosides in length, wherein the central gap segment consists of ten 2′-β-D-deoxynucleosides and the 5′ and 3′ wing segments each consists of five 2′-MOE modified nucleosides. The sugar motif for the gapmers is (from 5′ to 3′): eeeeeddddddddddeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar, and ‘e’ represents a 2′-MOE sugar moiety. The internucleoside linkage motif for the gapmers is (from 5′ to 3′): soooossssssssssooss; wherein each ‘o’ represents a phosphodiester internucleoside linkage and each ‘s’ represents a phosphorothioate internucleoside linkage. Each cytosine residue is a 5-methyl cytosine.

“Start site” indicates the 5′-most nucleoside to which the modified oligonucleotide is complementary in the target nucleic acid sequence. “Stop site” indicates the 3′-most nucleoside to which the modified oligonucleotide is complementary in the target nucleic acid sequence. Each modified oligonucleotide listed in the tables below is 100% complementary to either human SCN2A mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NM_001040142.2) or the human SCN2A genomic sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NC_000002.12 truncated from nucleotides 165127001 to 165395000), or to both. ‘N/A’ indicates that the modified oligonucleotide is not 100% complementary to that particular target nucleic acid sequence.

Cultured SH-SY5Y cells were treated with modified oligonucleotide at a concentration of 4000 or 5000 nM using electroporation at a density of 20,000 cells per well. After a treatment period of approximately 24 hours, total RNA was isolated from the cells and SCN2A RNA levels were measured by quantitative real-time RTPCR. SCN2A RNA levels were measured by Human primer probe set RTS36041 (forward sequence CCTTGAACCTGAAGCCTGTT, designated herein as SEQ ID NO: 10; reverse sequence CGAACCAATTGTGCTCCACTA, designated herein as SEQ ID NO: 11; probe sequence TTCCACCAGAGTTTCCCTTTGCCT, designated herein as SEQ ID NO: 12). SCN2A RNA levels were normalized to total RNA content, as measured by RIBOGREEN®. Reduction of SCN2A RNA is presented in the tables below as percent SCN2A RNA amount relative to the amount in untreated control cells (% control). Each table represents results from an individual assay plate. The values marked with an “T” indicate that the modified oligonucleotide is complementary to the amplicon region of the primer probe set. Additional assays may be used to measure the potency and efficacy of the modified oligonucleotides complementary to the amplicon region.

TABLE 2 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 5000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ SCN2A ID NO: ID NO: ID NO: ID NO: RNA SEQ Compound 1 Start 1 Stop 2 Start 2 Stop (% ID ID Site Site Site Site Sequence (5′ to 3′) control) NO 909933 N/A N/A 166831 166850 GACATATGTCTGAAGCAGCC  77 16 909939 N/A N/A 167084 167103 ATTGATAAGCTGGCACCAAG  27 17 909945  374  393 168919 168938 GTTTGGGTCTCTTAGCTTTC  10 18 909951 1064 1083 183411 183430 ACTGCAATCCTATTAGCGCA   7 19 909957 1188 1207 183535 183554 GTCCTATTGAAAGTAGTACC  22 20 909963 1840 1859 188649 188668 TTCCGATTTTCGGACTCTGT  23 21 909969 2080 2099 196286 196305 TCGGCTGTCATTGTCCTCAA  17 22 909975 2095 2114 196301 196320 GAACAGAGAGTCTCTTCGGC  21 23 909981 2367 2386 199924 199943 CTTTGCCTTGATGTAGGATC  10 24 909987 3437 3456 227431 227450 CTATGGTGGTATGGTTGGAA   8 25 909993 3647 3666 227641 227660 CCTCCATATCTGACTCGCTG  26 26 909999 3723 3742 238188 238207 TCTCCCTCGGCGGGAGCTCC  45 27 910005† 3804 3823 240222 240241 CAACACTTGAACTTCCGTAC   8 28 910010 4399 4418 247833 247852 GACCACGCTTACATCAAACA  24 29 910016 4423 4442 247857 247876 AGCTTTGCACTCACTGTAGT  28 30 910022 4587 4606 253592 253611 TACTTGGGTTGTAATTCTAC  13 31 910028 6030 6049 262558 262577 TTTTGCTTCAAGAGGTAGCG  61 32 910034 6196 6215 262724 262743 GGTCACACTATCATACGAGG  26 33 910040 6482 6501 263010 263029 CCCATCGATACTATTTCTCC  54 34 910046 6539 6558 263067 263086 GTAGCCATTACGCCTCTGCT  39 35 910052 6848 6867 263376 263395 GAATTGCAGCATGCCTCCAT  37 36 910057 7340 7359 263868 263887 CTATGTCAACCTTACCAAGA  39 37 910063 7687 7706 264215 264234 GTTTGCTGCAACCTATTGCT  37 38 910069 7994 8013 264522 264541 CCTACACTGCATCCTAGTCC  54 39 910075 8251 8270 264779 264798 GTTCTAGTGCCATATGGGTC  45 40 910081 8448 8467 264976 264995 ACCGTTCTTTATGGTAACAG  31 41 910087 8471 8490 264999 265018 TTGGCTTGATTGTAATGTGG  30 42 910093 N/A N/A 112411 112430 GGTACCCAATGTCTGTTAGA 120 43 910099   17   36 112430 112449 GTTCTGACAGTCATTCGATG  81 44 910105 N/A N/A  68142  68161 CACGCCAGTCTTCAGCAGTT  70 45 910111 N/A N/A  67941  67960 CACCTAAATCAGGGCAGTGC 101 46 910117 N/A N/A  67973  67992 GCATTCCCCGCTGCAGTAAG 125 47 910123 N/A N/A  81138  81157 GCAGAACAGTAGTATTCCTC 141 48 910129 N/A N/A   4279   4298 GGAGCTTGGTCTGTCAAATG  39 49 910135 N/A N/A  45144  45163 TTAGTTAAGTAATGGTTGGC  78 50  45306  45325 910141 N/A N/A  60136  60155 ATGTTCCACTAGTCTACCTC  81 51 910147 N/A N/A  86329  86348 GCACAAGACTAAACAGAGTG 106 52 910153 N/A N/A 104618 104637 GCACCAGTGGCCCCCTTAGT 119 53 910159 N/A N/A 114797 114816 GCCCCCCATGGACAGAAATT  66 54 910165 N/A N/A 118897 118916 GCAGCTTAGCTGAATGCCCT 112 55 910171 N/A N/A 121863 121882 CATGGTGCCCCTTAGTATGC  96 56 910177 N/A N/A 125285 125304 TGTTGACAGAAAGTCCCCTC  69 57 910183 N/A N/A 128499 128518 GGAGTTAAACCATAGAGCCA  63 58 128542 128561 910189 N/A N/A 131428 131447 CTCTCCAGCAAGCAACGGAC  74 59 910195 N/A N/A 135640 135659 CGCCCATTAATCACTTGTTG  78 60 910201 N/A N/A 142375 142394 CCACCATGTTTGCTTGGTGG  79 61 910207 N/A N/A 146958 146977 CCCCACCATATTGCTGCACC  86 62 910213 N/A N/A 150788 150807 GGGTGAAATAGCCTCTGTCG  75 63 910219 N/A N/A 154773 154792 CCTTGTGTGGCTGCCCACGA 115 64 910225 N/A N/A 158222 158241 GGTGGAACAGTCTACTGCCC  55 65 910231 N/A N/A 161691 161710 TAACCTGAATCCACTAGCCC  85 66 910237 N/A N/A 165153 165172 GTTCATGGTTTGTCCAGGGC  75 67 910243 N/A N/A 168057 168076 GGTCTGTAGCTCGGACCCCC  39 68 910249 N/A N/A 172552 172571 GACTATTAGCCTCACTGCCT  17 69 910255 N/A N/A 175759 175778 CCCCTGTCTCCGTGGAGCGA  24 70 910261 N/A N/A 179336 179355 CCCCGTGGCAGATTGGCACC  20 71 910267 N/A N/A 182818 182837 GCAGCACTCATGCTATCCCT  16 72 910273 N/A N/A 187114 187133 AGGACCGTATGCTTGTTCAC  36 73 910279 N/A N/A 189972 189991 GGCATTCTTCATAGGCAACT  12 74 910285 N/A N/A 196488 196507 GCCTCACCTCTGGTAGGAGC  43 75 910291 N/A N/A 200571 200590 TCACAGATTAAGCTGTCCCC  17 76 910297 N/A N/A 204970 204989 TGTCCCCTCCCTACATAGTC  39 77 910303 N/A N/A 209576 209595 GCTCCCATTTACCCTAATCC  25 78 910309 N/A N/A 214387 214406 ATATCACCACTGTGGGCCGG  55 79 910315 N/A N/A 218046 218065 TGGTCTAAACTATACATGGC  19 80 910321 N/A N/A 223836 223855 TGGACTTCCTTTGTTACCGA  15 81 910327 N/A N/A 228592 228611 CTTCCTCGCCAAACAGTTCG  40 82 910333 N/A N/A 231798 231817 ACACCCTAGGAGCAAGAGTT  20 83 910339 N/A N/A 234815 234834 GAACTGTAGTTTAACTGTGG  32 84 910345 N/A N/A 235696 235715 CGTACTCTAGGCCCTATGGA  13 85 910351 N/A N/A 239653 239672 GACCTCGGCTCATGCACTGC  45 86 910357 N/A N/A 242417 242436 AGCTCCATACAAGGACCTAA  20 87 910363 N/A N/A 246343 246362 GGCATTCAGTCTTACCCTCA  14 88 910369 N/A N/A 248839 248858 CATTGTGTATGTCTATAGGG  19 89 910375 N/A N/A 252486 252505 CCCTTGGTGTACCCTTCTCA  25 90 910381 N/A N/A 255582 255601 GCTATTCTTACAGCAGGTCG  11 91 910387 N/A N/A 258291 258310 TAACCTCTGTTGGGCTGCCT  53 92 910393 N/A N/A 259528 259547 CAGGTAAGTAGTGTAAATAG  27 93

TABLE 3 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 5000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SCN2A SEQ Compound 1 Start 1 Stop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) control) NO 909934 N/A N/A 166889 166908 TAACTACCACTAGAGGGCGG  96  94 909940 N/A N/A 167087 167106 GGGATTGATAAGCTGGCACC  24  95 909946  381  400 168926 168945 CGTTCCTGTTTGGGTCTCTT   7  96 909952 1066 1085 183413 183432 CAACTGCAATCCTATTAGCG  31  97 909958 1195 1214 183542 183561 GCTCACTGTCCTATTGAAAG   3  98 909964 1842 1861 188651 188670 GATTCCGATTTTCGGACTCT  38  99 909970 2082 2101 196288 196307 CTTCGGCTGTCATTGTCCTC  22 100 909976 2138 2157 196344 196363 GGCTGACATTGCTGTGGCGC  15 101 909982 2490 2509 204392 204411 GGTTTACAACAGTCCCAAAT  26 102 909988 3471 3490 227465 227484 CCGTCTTTGAGATAATTGAG   5 103 909994 3705 3724 238170 238189 CCAATATCAACCGTGCTGCC  47 104 910000 3725 3744 238190 238209 GTTCTCCCTCGGCGGGAGCT  49 105 910006† 3806 3825 240224 240243 GACAACACTTGAACTTCCGT   5 106 910011 4403 4422 247837 247856 TGTTGACCACGCTTACATCA  28 107 910017 4440 4459 247874 247893 TGATTGCTCTCAATGAGAGC  73 108 910023 4598 4617 253603 253622 GGTTGTCTTCATACTTGGGT  11 109 910029 6091 6110 262619 262638 GGGTGTTCCATCACATTCTT  59 110 910035 6359 6378 262887 262906 GTGGGAGTCCTGTTGACACA  50 111 910041 6486 6505 263014 263033 ACCTCCCATCGATACTATTT  46 112 910047 6543 6562 263071 263090 CTGAGTAGCCATTACGCCTC  45 113 910053 6944 6963 263472 263491 CGAATAGCTATTTAAGCACC  38 114 910058 7344 7363 263872 263891 TATACTATGTCAACCTTACC  51 115 910064 7753 7772 264281 264300 GTCGGGCTTTTCATCATTGA  27 116 910070 8031 8050 264559 264578 TGTGTGCAAGTTTACAGTAC  27 117 910076 8253 8272 264781 264800 CAGTTCTAGTGCCATATGGG  23 118 910082 8453 8472 264981 265000 GGTTTACCGTTCTTTATGGT  41 119 910088 8676 8695 265204 265223 GTAGTTATCCAATACACTCT  30 120 910094    2   21 112415 112434 CGATGGTACCCAATGTCTGT  73 121 910100   19   38 112432 112451 CTGTTCTGACAGTCATTCGA  87 122 910106 N/A N/A  68149  68168 GACAGACCACGCCAGTCTTC 125 123 910112 N/A N/A  67945  67964 TCCACACCTAAATCAGGGCA  88 124 910118 N/A N/A  67975  67994 CTGCATTCCCCGCTGCAGTA  87 125 910124 N/A N/A  81145  81164 TAGTCCAGCAGAACAGTAGT  96 126 910130 N/A N/A  10920  10939 GGCCATGGAGCACTACCCCA 143 127 910136 N/A N/A  45145  45164 GTTAGTTAAGTAATGGTTGG  95 128 N/A N/A  45307  45326 910142 N/A N/A  61499  61518 CGCGCCCTGCTGCACAGGTG 177 129 910148 N/A N/A  88505  88524 CTACCCTTTTATTTGGGTAG  88 130 910154 N/A N/A 110407 110426 ATGCTCACAATCTAGACTCC 100 131 910160 N/A N/A 115370 115389 GGCCTCCTATGATATTGTTA  68 132 910166 N/A N/A 119784 119803 GGCATGATTGCTGGGCATCA  70 133 910172 N/A N/A 122320 122339 CCAGTGCTTTGCTCCACACG  68 134 910178 N/A N/A 125962 125981 GCCCGTCCCCACTGACCAAT  72 135 910184 N/A N/A 128500 128519 TGGAGTTAAACCATAGAGCC  78 136 N/A N/A 128543 128562 910190 N/A N/A 131799 131818 GCCTACTATAATAGCCCCCA  75 137 910196 N/A N/A 137199 137218 TAGTGCAGGATTTTGCCCAC  81 138 910202 N/A N/A 142673 142692 TGGTCACATATGAGGTCCAA  93 139 910208 N/A N/A 147833 147852 AGCCCGGGCTGCCCGGAAAA 111 140 910214 N/A N/A 151191 151210 ATAATGTGCTCACGGTCTTC  91 141 910220 N/A N/A 155700 155719 CCCCAGCTGCGAGTAGTGCC  64 142 910226 N/A N/A 159287 159306 GGTGAGCCCCATGTTCAGCC  75 143 910232 N/A N/A 162056 162075 GTGGTTGTGGATAAGTGCGC  91 144 910238 N/A N/A 165156 165175 TTGGTTCATGGTTTGTCCAG  81 145 910244 N/A N/A 168609 168628 GAATCTCATATGTGCATCCA  22 146 910250 N/A N/A 173305 173324 ATGTTGCATCCCAATGCTTA  21 147 910256 N/A N/A 176729 176748 AGGGTCAAGTTTTTACGCTT  10 148 910262 N/A N/A 180045 180064 GCAGGTATAGCCAATGCCCT  29 149 910268 N/A N/A 183262 183281 AACAGCTATTTTACCGGCAA  34 150 910274 N/A N/A 187485 187504 CCACCTCTGGTGATACTGCA  33 151 910280 N/A N/A 191068 191087 CAGACACGATGGGCCCTCCA  34 152 910286 N/A N/A 197133 197152 GTGATTGGTTTTGGGCCACT  15 153 910292 N/A N/A 201329 201348 GCTAACGCAGGCGAGGTTGG  17 154 910298 N/A N/A 205501 205520 GATACAGTTTCCCAACTGCG  19 155 910304 N/A N/A 209963 209982 CTATGTACCGCTTTAATCTA  36 156 910310 N/A N/A 214947 214966 CCTAGCAGTGCGGGCTTCCA  42 157 910316 N/A N/A 218623 218642 CGGTGTGCTGTGACCCATCT  21 158 910322 N/A N/A 224270 224289 GCAGCCAATCTACCCGTGGT  26 159 910328 N/A N/A 229258 229277 GTAATTCTTTGCCCCAGGAC  14 160 910334 N/A N/A 232338 232357 ACCCTTGCCTCTTTCCGAGA  37 161 910340 N/A N/A 235294 235313 GCTCCCTTTCATTTTAGTGC  22 162 910346 N/A N/A 236310 236329 GACTTCGGGTGACCCCAAGG  33 163 910352 N/A N/A 240745 240764 GCTCCTACCGGCACCCATGC  47 164 910358 N/A N/A 242892 242911 TTGGTCTCAGTGTACCCCCA  22 165 910364 N/A N/A 246704 246723 CACAGCGGAGTAGTGAAGAA  32 166 910370 N/A N/A 249680 249699 CCCTTTTCAACCCCCCTTGG  57 167 910376 N/A N/A 253093 253112 GAACAGTGGCGGCCAGTAGT  13 168 910382 N/A N/A 255973 255992 ACACCCCTACCACTACAGGT  47 169 910388 N/A N/A 259152 259171 TCTTAATGCTACCTCATAGC  76 170 N/A N/A 260854 260873 910394 N/A N/A 260307 260326 CAGGAGTATGACCAGGTACA  52 171

TABLE 4 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 5000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SCN2A SEQ Compound 1 Start 1 Stop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) control) NO 909935 N/A N/A 166891 166910 TGTAACTACCACTAGAGGGC  81 172 909941 N/A N/A 167093 167112 GAGTTTGGGATTGATAAGCT  29 173 909947  566  585 170037 170056 ATCGAGAGATTGCTTTCCCT   9 174 909953 1116 1135 183463 183482 GAATTATCTGGAGGCCATTG  23 175 909959 1671 1690 188480 188499 GATTCAGCAGATGCGGCTGC  28 176 909965 1989 2008 196195 196214 AGGCTCGCCCTACTGTTGCG  21 177 909971 2084 2103 196290 196309 CTCTTCGGCTGTCATTGTCC  32 178 909977 2236 2255 196442 196461 GCCCCCGACCAGGGAGACCA  49 179 909983 2494 2513 204396 204415 CCATGGTTTACAACAGTCCC  28 180 909989 3499 3518 227493 227512 GCTGCCTATGCCACTAGTAG  12 181 909995 3708 3727 238173 238192 GCTCCAATATCAACCGTGCT  21 182 910001 3729 3748 238194 238213 GGCTGTTCTCCCTCGGCGGG  35 183 910007† 3880 3899 240298 240317 GTGCTCCACTATCTTATAGC   3 184 910012 4406 4425 247840 247859 AGTTGTTGACCACGCTTACA  20 185 910018 4443 4462 247877 247896 GTTTGATTGCTCTCAATGAG  34 186 910024 5020 5039 259936 259955 GTAACGAAGAGAGATCAGTT  37 187 910030 6095 6114 262623 262642 TGATGGGTGTTCCATCACAT  67 188 910036 6362 6381 262890 262909 CCTGTGGGAGTCCTGTTGAC  48 189 910042 6489 6508 263017 263036 GAAACCTCCCATCGATACTA  49 190 910048 6545 6564 263073 263092 GTCTGAGTAGCCATTACGCC  66 191 910054 6946 6965 263474 263493 TACGAATAGCTATTTAAGCA  37 192 910059 7528 7547 264056 264075 GCTTCAAACTATAATGGAAC  33 193 910065 7756 7775 264284 264303 ACAGTCGGGCTTTTCATCAT  23 194 910071 8173 8192 264701 264720 GACTAGGTGGAAACATTGGA  32 195 910077 8257 8276 264785 264804 GATACAGTTCTAGTGCCATA  26 196 910083 8455 8474 264983 265002 GTGGTTTACCGTTCTTTATG  23 197 910089 8705 8724 265233 265252 CCATATCTAGCTTTTTGGCC  56 198 910095    6   25 112419 112438 CATTCGATGGTACCCAATGT  61 199 910101 N/A N/A  68125  68144 GTTTGGTTGCTACAATCCCT  90 200 910107 N/A N/A  68151  68170 CAGACAGACCACGCCAGTCT 105 201 910113 N/A N/A  67952  67971 GGCATCATCCACACCTAAAT 146 202 910119 N/A N/A  67979  67998 TACTCTGCATTCCCCGCTGC 129 203 910125 N/A N/A  81153  81172 CACTTCATTAGTCCAGCAGA  84 204 910131 N/A N/A  13052  13071 ATTGGCCCACATATGTCAAT  82 205 910137 N/A N/A  45146  45165 GGTTAGTTAAGTAATGGTTG  82 206 910143 N/A N/A  66809  66828 GCTAGACAAATCCCAATCCT  98 207 910149 N/A N/A  92636  92655 GCTTTCCAGTGCGCCCCAGG 100 208 910155 N/A N/A 110587 110606 GCACGCCACCTCATGCCCCC 106 209 910161 N/A N/A 115772 115791 GTCTCTTCCACGACCTTGGT  92 210 910167 N/A N/A 119798 119817 ATCTAGGGACATGTGGCATG  86 211 910173 N/A N/A 122696 122715 GACTCTTTAGGAGAGTTAAC  75 212 910179 N/A N/A 126382 126401 AGGCTATAAGTGGCCTCTCA  48 213 910185 N/A N/A 128584 128603 GGGTTAAACCATAGAGCCAT 100 214 910191 N/A N/A 132879 132898 GATTCCGTGAATGGGTCTGG  77 215 910197 N/A N/A 137619 137638 CCTATCAGAGGGTGTGTGAC  74 216 910203 N/A N/A 143552 143571 GGCGATAGTAGCCAGAGTCC  60 217 910209 N/A N/A 147840 147859 ATAGCCAAGCCCGGGCTGCC  97 218 910215 N/A N/A 151615 151634 CCTCTTACCAACCCCCACGA  77 219 910221 N/A N/A 155704 155723 GAGGCCCCAGCTGCGAGTAG  94 220 910227 N/A N/A 160224 160243 CGCCGTAACCAGGCCATAAC  63 221 910233 N/A N/A 162830 162849 CTCTCCCATTGATTCTAGCC  56 222 910239 N/A N/A 166137 166156 GATATTAGCCTCAGCCCCAG  72 223 910245 N/A N/A 169307 169326 TTCCCGCGCTGGAGGATGCC  28 224 910251 N/A N/A 173911 173930 ATCGGTCCCAGTCTCCTTGC  15 225 910257 N/A N/A 176731 176750 CTAGGGTCAAGTTTTTACGC  14 226 910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA   7 227 910269 N/A N/A 183973 183992 GCATCAACCAAATAGGGCCA   5 228 910275 N/A N/A 188458 188477 CTGCCGCCTAGAAGGGCGCA  79 229 910281 N/A N/A 191544 191563 GTGCCCCATCCGTTAGCATC  33 230 910287 N/A N/A 197777 197796 AGGTTCAGTAACCAGCATAC  35 231 910293 N/A N/A 201697 201716 AACCCCATGTCACATAGTTC  44 232 910299 N/A N/A 206261 206280 CGTAAGACCAGCCCCAGCTT  39 233 910305 N/A N/A 210937 210956 AGCTGTCTACATACCCCTGA  33 234 910311 N/A N/A 215590 215609 GGTGGTATGGCAATCCAATT  18 235 910317 N/A N/A 220917 220936 ATCCCTCAGTCACTGGGTAC  36 236 910323 N/A N/A 225034 225053 ATCAATCCTTCCCCAGGGCG  27 237 910329 N/A N/A 229738 229757 CGCTCTTTTGGAAAACCCAC  13 238 910335 N/A N/A 232818 232837 TGCTCAGTAGATTACCAGTG  11 239 910341 N/A N/A 235624 235643 GGATAATACACCAATATAGT  19 240 910347 N/A N/A 237210 237229 GGCCACAGCATTCTCGGACC  39 241 910353 N/A N/A 241447 241466 AGGACGGGTACCTGGCGAGG  58 242 910359 N/A N/A 243777 243796 GGCTACTTGGTCAATAGCCA  63 243 910365 N/A N/A 247097 247116 ACACCATTCATCTCTAGTTG  33 244 910371 N/A N/A 250433 250452 TGTTTTGCGATATGCATTGA  17 245 910377 N/A N/A 254187 254206 TATTCTTACAGCAGGTCGAG  21 246 255580 255599 910383 N/A N/A 256523 256542 GTTAACGGTTTCTTACTGCT  19 247 910389 N/A N/A 259509 259528 GGGAAGCTCCATGTCAGATC  28 248 910395 N/A N/A 260723 260742 CCCCAAATAGGTAGAACCTT  56 249

TABLE 5 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 5000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SCN2A SEQ Compound 1 Start 1 Stop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) control) NO 909936 N/A N/A 166893 166912 ATTGTAACTACCACTAGAGG  65 250 909942  285  304 168830 168849 GGCGGTACCAGCACTGACTG  20 251 909948 1055 1074 183402 183421 CTATTAGCGCAAACACGCTT  29 252 909954 1174 1193 183521 183540 AGTACCATTCCCATCCAATG  17 253 909960 1674 1693 188483 188502 CTTGATTCAGCAGATGCGGC  38 254 909966 1993 2012 196199 196218 GAAAAGGCTCGCCCTACTGT  39 255 909972 2088 2107 196294 196313 GAGTCTCTTCGGCTGTCATT  39 256 909978 2243 2262 196449 196468 TAGAAGGGCCCCCGACCAGG  52 257 909984 2503 2522 204405 204424 CACCTTTAACCATGGTTTAC  60 258 909990 3531 3550 227525 227544 TCACTTTCATCCACGACATA  22 259 909996 3712 3731 238177 238196 GGGAGCTCCAATATCAACCG  18 260 910002† 3752 3771 238217 238236 GGGATTCCTCAGGTTCAACC  19 261 910008 4128 4147 246225 246244 GTTAAGCTAACCAGTGAGAC  39 262 910013 4410 4429 247844 247863 CTGTAGTTGTTGACCACGCT  15 263 910019 4447 4466 247881 247900 GGCAGTTTGATTGCTCTCAA  26 264 910025 5031 5050 259947 259966 GTGAAATAGTAGTAACGAAG  38 265 910031 6098 6117 262626 262645 CTTTGATGGGTGTTCCATCA  64 266 910037 6368 6387 262896 262915 AGACCTCCTGTGGGAGTCCT  61 267 910043 6491 6510 263019 263038 TAGAAACCTCCCATCGATAC  46 268 910049 6564 6583 263092 263111 CTTTAAATTGGTTCCTATCG  80 269 910055 7173 7192 263701 263720 GATAGTCATGCTGCTGGGAC  45 270 910060 7607 7626 264135 264154 GGCTTCCCATATTAGACTTC  25 271 910066 7758 7777 264286 264305 GTACAGTCGGGCTTTTCATC  35 272 910072 8243 8262 264771 264790 GCCATATGGGTCAATAAGAT  19 273 910078 8275 8294 264803 264822 GGATCCCATATTATATCTGA  60 274 910084 8460 8479 264988 265007 GTAATGTGGTTTACCGTTCT  36 275 910090 8723 8742 265251 265270 CCACTAGTCTACCTGATGCC  78 276 910096    8   27 112421 112440 GTCATTCGATGGTACCCAAT  83 277 910102 N/A N/A  68127  68146 CAGTTTGGTTGCTACAATCC 124 278 910108 N/A N/A  67895  67914 CCAATGATGTGCTCGGAGCC 115 279 910114 N/A N/A  67958  67977 GTAAGTGGCATCATCCACAC 124 280 910120 N/A N/A  68026  68045 GAGCACTGAACAGCATCCCC  82 281 910126 N/A N/A  81155  81174 GGCACTTCATTAGTCCAGCA 105 282 910132 N/A N/A  25045  25064 TCGGGACATAGTTATGTTGT  73 283 910138 N/A N/A  45303  45322 GTTAAGTAATGGTTGGCTCT 116 284 910144 N/A N/A  72609  72628 ACCACAAGTTTCAATGTGCC  69 285 910150 N/A N/A  97682  97701 AACTAATGAGGTCCTAGGCT  97 286 910156 N/A N/A 112991 113010 GAGCCACTGCCATGTTAATC  65 287 910162 N/A N/A 116308 116327 CCCGGCCATGACATTGACTC  72 288 910168 N/A N/A 120435 120454 GGCAATAGGGTGGTCATCAG  79 289 910174 N/A N/A 123275 123294 GTAGGACATAGTTATGTTGT  59 290 910180 N/A N/A 127396 127415 TTTCCGAAAGAACACCCTCA  84 291 910186 N/A N/A 128915 128934 CCATCAAGTTTCTGGTAGGG  57 292 910192 N/A N/A 133286 133305 TGCCCGCACTCCATGGATCA  78 293 910198 N/A N/A 138615 138634 CTATGGAGGTTGATAGTGGG 101 294 910204 N/A N/A 144488 144507 TTGGTTACACCAAGCCAGGC  77 295 910210 N/A N/A 148389 148408 GTGGTACAAATTGCTCCAGG  65 296 910216 N/A N/A 152213 152232 GATGGAAGCTAACTCCCCCT  87 297 910222 N/A N/A 156329 156348 GATCCCTAGTCCTGAGTGCT 100 298 910228 N/A N/A 160587 160606 ACGGTCAGGTGGTTACTAAA  86 299 910234 N/A N/A 163742 163761 GTCCTACTGCAATCAAGCGC  87 300 910240 N/A N/A 166626 166645 GTAGTGCACTGCTTAATGGC  93 301 910246 N/A N/A 170179 170198 GTGTAGCTCAATAACTTGGT  11 302 910252 N/A N/A 174379 174398 TACTAGTGTGATTTGGAGGG  26 303 910258 N/A N/A 177000 177019 ATGCTGCATTATGGACTCGG   9 304 910264 N/A N/A 181552 181571 CACTTCCAGGTTGGTCCCCC  15 305 910270 N/A N/A 184951 184970 GCCACCCTGTTTAGGTGGCA  91 306 910276 N/A N/A 188459 188478 GCTGCCGCCTAGAAGGGCGC  72 307 910282 N/A N/A 192994 193013 CCGATGAGGCTTTGTTTGGA  16 308 910288 N/A N/A 198263 198282 GCTTCAAGCTGGCCCCAACT  34 309 910294 N/A N/A 202319 202338 GCGCTTCTAACTCACCCTCC  32 310 910300 N/A N/A 207031 207050 GCGCTTGTTACTCCCTAGGA  16 311 910306 N/A N/A 211928 211947 CGCCCGGCTAGATGTAGGGT  47 312 910312 N/A N/A 216181 216200 GTAACCGTGTACAGCCTCTG  22 313 910318 N/A N/A 221714 221733 CAGCCCCAGTCAAGATAACT  52 314 910324 N/A N/A 226106 226125 ATAGGCTCCACCAGTATGAA  28 315 910330 N/A N/A 230447 230466 GTCCACTCAGTCTGCCTTAT  10 316 910336 N/A N/A 233677 233696 GTAGCATAGCCCTTGCCTAG  19 317 910342 N/A N/A 235631 235650 GCCATATGGATAATACACCA   9 318 910348 N/A N/A 238060 238079 ATTAGGTGTGCCCCCCCCCC  69 319 910354 N/A N/A 241551 241570 CAATAGCGAATCAGTGTGAA  34 320 910360 N/A N/A 244598 244617 CCCGCCCTGCATGTCATGCA  68 321 910366 N/A N/A 247538 247557 ACTAGACTCTGGTAGCTCCA  12 322 910372 N/A N/A 250934 250953 TGACCAGGACTATCAGAGCC  23 323 910378 N/A N/A 254189 254208 GTTATTCTTACAGCAGGTCG  15 324 910384 N/A N/A 257640 257659 CCACTTGTTTTGAGGCCCCT  49 325 910390 N/A N/A 259516 259535 GTAAATAGGGAAGCTCCATG  43 326 910396 N/A N/A 260802 260821 GTTACAATGTTCTATTCGAC  49 327

TABLE 6 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 5000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SCN2A SEQ Compound 1 Start 1 Stop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) control) NO 909533 4131 4150 246228 246247 GCAGTTAAGCTAACCAGTGA  15 328 909937 N/A N/A 166922 166941 TTCCTGTACAGGGACTACAA  68 329 909943  316  335 168861 168880 CCTGGTAAAGAAGCGGAAGC  31 330 909949 1058 1077 183405 183424 ATCCTATTAGCGCAAACACG  24 331 909955 1177 1196 183524 183543 AGTAGTACCATTCCCATCCA  11 332 909961 1676 1695 188485 188504 CTCTTGATTCAGCAGATGCG  28 333 909967 1996 2015 196202 196221 GCTGAAAAGGCTCGCCCTAC  13 334 909973 2090 2109 196296 196315 GAGAGTCTCTTCGGCTGTCA  30 335 909979 2324 2343 199881 199900 GATAAGAACTGGACCGTCTC  25 336 909985 3430 3449 227424 227443 GGTATGGTTGGAAATACAGC  11 337 909991 3641 3660 227635 227654 TATCTGACTCGCTGCTGAAT  47 338 909997 3715 3734 238180 238199 GGCGGGAGCTCCAATATCAA  37 339 910003† 3797 3816 240215 240234 TGAACTTCCGTACACAGTCT   7 340 910014 4414 4433 247848 247867 CTCACTGTAGTTGTTGACCA  19 341 910020 4450 4469 247884 247903 CCTGGCAGTTTGATTGCTCT  24 342 910026 5033 5052 259949 259968 TAGTGAAATAGTAGTAACGA  31 343 910032 6149 6168 262677 262696 CGGTTTTCTCTGGAGTTGAA  45 344 910038 6373 6392 262901 262920 GGCATAGACCTCCTGTGGGA  54 345 910044 6493 6512 263021 263040 AATAGAAACCTCCCATCGAT  78 346 910050 6569 6588 263097 263116 CCCCCCTTTAAATTGGTTCC  38 347 910056 7247 7266 263775 263794 GGTCAATTCAGGCTTCTTAG  23 348 910061 7610 7629 264138 264157 TATGGCTTCCCATATTAGAC  20 349 910067 7762 7781 264290 264309 GTTTGTACAGTCGGGCTTTT  24 350 910073 8245 8264 264773 264792 GTGCCATATGGGTCAATAAG  20 351 910079 8323 8342 264851 264870 GGTAATATAACTTCACTACC  35 352 910085 8464 8483 264992 265011 GATTGTAATGTGGTTTACCG  37 353 910091 8725 8744 265253 265272 TTCCACTAGTCTACCTGATG  58 354 910097   10   29 112423 112442 CAGTCATTCGATGGTACCCA  48 355 910103 N/A N/A  68132  68151 TTCAGCAGTTTGGTTGCTAC  91 356 910109 N/A N/A  67897  67916 TGCCAATGATGTGCTCGGAG  72 357 910115 N/A N/A  67966  67985 CCGCTGCAGTAAGTGGCATC  81 358 910121 N/A N/A  81130  81149 GTAGTATTCCTCCAATCACT  91 359 910127 N/A N/A  81159  81178 GAGTGGCACTTCATTAGTCC  64 360 910133 N/A N/A  38868  38887 AGATCAATTGAATTGTTGGG  69 361 910139 N/A N/A  49570  49589 CAAGTTCAAATGTGTAGTGC  68 362 910145 N/A N/A  83239  83258 TCAGGACAAGCTATCAAGTA  59 363 910151 N/A N/A 101360 101379 ATTGGCAGGCTATGCTTAAT 105 364 910157 N/A N/A 113713 113732 ATCCTGATGCACCTCCACCG  45 365 910163 N/A N/A 116964 116983 AAGAGCCACGGTGGCCCATC 116 366 910169 N/A N/A 121086 121105 GGTGGCTTGAGCAGGGTAGC 122 367 910175 N/A N/A 123464 123483 AGCAAGAGGGCACCGTTTCC 100 368 910181 N/A N/A 128203 128222 AACTGCAGTTGATATACCCC  58 369 910187 N/A N/A 129655 129674 GCAAGGGAGTCCAGTTGGAT  43 370 910193 N/A N/A 134589 134608 GGTGTACCCCACTTGAGGTG  64 371 910199 N/A N/A 139454 139473 GGCTTTCCCGGCCCTTACTC  91 372 910205 N/A N/A 145496 145515 GGTCTGCAGGTTTGATCCCT  98 373 910211 N/A N/A 149375 149394 ATTAGTTACCTTGGAGGGCC  33 374 910217 N/A N/A 152584 152603 CCGTTTGTTTCCCATCCATC  69 375 910223 N/A N/A 157003 157022 GCATAGGAGACCATGGGTTC  45 376 910229 N/A N/A 161047 161066 GGATGGAATAGGTTGTGCAC  30 377 910235 N/A N/A 164328 164347 GACAGACAAGTCCCGGTGGC  94 378 910241 N/A N/A 167416 167435 TACCAGCTAGCAGACTGCCC  43 379 910247 N/A N/A 171039 171058 CGTGTAAATGCCCCTGCCCC  22 380 910253 N/A N/A 174686 174705 TTACAGCAGTTGCTGCTAGA  23 381 910259 N/A N/A 177827 177846 CGCTAGGAGGTCTGATCCCT  32 382 910265 N/A N/A 181873 181892 ATGCTTGGTCTGTCAAGGCA  13 383 910271 N/A N/A 186058 186077 TCAGGCACCTCGCATGTGAG  36 384 910277 N/A N/A 189147 189166 GAACAACCCCGCAGGTGGCC  22 385 910283 N/A N/A 193733 193752 GTGCCCTGTATCTCTGCGGC  19 386 910289 N/A N/A 199584 199603 GGAGGGACCAGGTCCACTAC  51 387 910295 N/A N/A 203237 203256 ATGTGGCCACCACCTCTTAG  32 388 910301 N/A N/A 208608 208627 GCTCTACCTTTAGGCCTATG  21 389 910307 N/A N/A 212293 212312 GGGCAAGAATTCACTACCTC  20 390 910313 N/A N/A 216623 216642 TGTCAGGCTGAAAGTAGTGC  16 391 910319 N/A N/A 222077 222096 GTAACCCTATGGCACTTTCT  15 392 910325 N/A N/A 226685 226704 TTGTAGTGCCTCCTGCCCAC  36 393 910331 N/A N/A 230983 231002 GTATGACTCAGCATAATAGC  31 394 910337 N/A N/A 234351 234370 TGTAGGTTCAAGATAGTGCT  24 395 910343 N/A N/A 235679 235698 GGATAATACACCAATATGGA  20 396 910349 N/A N/A 238413 238432 ATGTACAGTTGTTGGATAGG  48 397 910355 N/A N/A 241553 241572 GGCAATAGCGAATCAGTGTG  10 398 910361 N/A N/A 245087 245106 TATAAGGACCTGTAGTACTT  43 399 910367 N/A N/A 248036 248055 TCTAACAGGTGGATATCTCA  22 400 910373 N/A N/A 251285 251304 AGCTAGCTGCTGGTGCTAGG  24 401 910379 N/A N/A 254815 254834 GCGATTCTCCTGGCAGCAAC  33 402 910385 N/A N/A 258128 258147 TCCAATGGTGATTTTTGGAC  36 403 910391 N/A N/A 259525 259544 GTAAGTAGTGTAAATAGGGA  18 404 260902 260921 910397 N/A N/A 260852 260871 TTAATGCTACCTCATAGCAC  39 405

TABLE 7 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 5000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SCN2A SEQ Compound 1 Start 1 Stop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) control) NO 909603 7336 7355 263864 263883 GTCAACCTTACCAAGAGCAG  23 406 909938 N/A N/A 166924 166943 ATTTCCTGTACAGGGACTAC  85 407 909944  320  339 168865 168884 ATTCCCTGGTAAAGAAGCGG  25 408 909950 1061 1080 183408 183427 GCAATCCTATTAGCGCAAAC  12 409 909956 1186 1205 183533 183552 CCTATTGAAAGTAGTACCAT  14 410 909962 1838 1857 188647 188666 CCGATTTTCGGACTCTGTCA  14 411 909968 2023 2042 196229 196248 GCCAATGTCCTTTGCTCGAC  30 412 909974 2092 2111 196298 196317 CAGAGAGTCTCTTCGGCTGT  35 413 909980 2363 2382 199920 199939 GCCTTGATGTAGGATCTTCC   6 414 909986 3433 3452 227427 227446 GGTGGTATGGTTGGAAATAC  21 415 909992 3644 3663 227638 227657 CCATATCTGACTCGCTGCTG  25 416 909998 3717 3736 238182 238201 TCGGCGGGAGCTCCAATATC  44 417 910004† 3799 3818 240217 240236 CTTGAACTTCCGTACACAGT  15 418 910009 4397 4416 247831 247850 CCACGCTTACATCAAACATC  30 419 910015 4417 4436 247851 247870 GCACTCACTGTAGTTGTTGA   8 420 910021 4499 4518 247933 247952 ACAGATATCCAAGTCCTACG  34 421 910027 6003 6022 262531 262550 GCCCTCTGGATAATAATAGC  53 422 910033 6156 6175 262684 262703 GTCATATCGGTTTTCTCTGG  40 423 910039 6480 6499 263008 263027 CATCGATACTATTTCTCCAG  47 424 910045 6537 6556 263065 263084 AGCCATTACGCCTCTGCTCT  44 425 910051 6572 6591 263100 263119 CCTCCCCCCTTTAAATTGGT  58 426 910062 7655 7674 264183 264202 GAATGAGGTCTTGGTAGAAC  25 427 910068 7769 7788 264297 264316 GCAACATGTTTGTACAGTCG  15 428 910074 8248 8267 264776 264795 CTAGTGCCATATGGGTCAAT  27 429 910080 8446 8465 264974 264993 CGTTCTTTATGGTAACAGCA  16 430 910086 8469 8488 264997 265016 GGCTTGATTGTAATGTGGTT  34 431 910092 8731 8750 265259 265278 GTAACTTTCCACTAGTCTAC  68 432 910098   15   34 112428 112447 TCTGACAGTCATTCGATGGT  46 433 910104 N/A N/A  68140  68159 CGCCAGTCTTCAGCAGTTTG  76 434 910110 N/A N/A  67899  67918 GGTGCCAATGATGTGCTCGG 112 435 910116 N/A N/A  67969  67988 TCCCCGCTGCAGTAAGTGGC 108 436 910122 N/A N/A  81132  81151 CAGTAGTATTCCTCCAATCA  89 437 910128 N/A N/A  81162  81181 GTGGAGTGGCACTTCATTAG  51 438 910134 N/A N/A  45141  45160 GTTAAGTAATGGTTGGCACC 112 439 910140 N/A N/A  58777  58796 GTCAAGTTTTTGAACTGACC  96 440 910146 N/A N/A  83241  83260 GATCAGGACAAGCTATCAAG  64 441 910152 N/A N/A 102749 102768 GTTACAAAAGTAGGGACTCA  89 442 910158 N/A N/A 114092 114111 GTCTATGCCATCCTGATATG  85 443 910164 N/A N/A 118010 118029 GAGGGATAGTGTCAGTCTTC  67 444 910170 N/A N/A 121443 121462 AGGAGGTTAGTCATGCAAGT  70 445 910176 N/A N/A 124678 124697 GAGTGCACCCCAAGGCTAGC  57 446 910182 N/A N/A 128498 128517 GAGTTAAACCATAGAGCCAT  36 447 128541 128560 910188 N/A N/A 130065 130084 TCCCATGGTTGGTCCTAGCC  83 448 910194 N/A N/A 135044 135063 ATCCAGACCGTATTGCAACC  73 449 910200 N/A N/A 141973 141992 CTACCCAGTAGCCCCTGGTA 103 450 910206 N/A N/A 146430 146449 GTTGGCACTATAACCAATGC  62 451 910212 N/A N/A 150028 150047 TGCTCTGTCGACACCTGTCT  56 452 910218 N/A N/A 153536 153555 CACCGGCACTTCAGACTTGG  82 453 910224 N/A N/A 157533 157552 GTAGATCTGAATGTCTGGGC  74 454 910230 N/A N/A 161147 161166 TTAGGACAAGCTATCACCAG  44 455 910236 N/A N/A 164991 165010 GTAGCAGCTCTAGCCTCCCA  39 456 910242 N/A N/A 168052 168071 GTAGCTCGGACCCCCTGGCT  42 457 910248 N/A N/A 171979 171998 TCATCATTCAGATGCACGAC  20 458 910254 N/A N/A 174799 174818 GGTCTAAACTCTGGTGCTAT  20 459 910260 N/A N/A 178626 178645 GGATGGTTCCTCCCCTTAGC  28 460 910266 N/A N/A 182069 182088 ATTTCATGAGTGTCGCCATC  17 461 910272 N/A N/A 186570 186589 TCAATAACGGCAAGTCTGCT  54 462 910278 N/A N/A 189529 189548 TAGGTATTAAGGTTTCACTC  21 463 910284 N/A N/A 195317 195336 GAGGCTCGGGTCTCCCAGTG  38 464 910290 N/A N/A 200118 200137 ATCCATGAGTTATGCACGGA  26 465 910296 N/A N/A 203948 203967 GATATCTCAGGAGATGTCCT  38 466 910302 N/A N/A 209203 209222 GTGGTAACTCTACCCCAAAC  33 467 910308 N/A N/A 213398 213417 AGGTGGTTACCTCAGAGACC  25 468 910314 N/A N/A 217259 217278 GTGACTTGCTACCATAGAGC  17 469 910320 N/A N/A 222990 223009 CTAGGCTGGCAGTCCCATCC  35 470 910326 N/A N/A 228033 228052 GCAACTACCCTCTCATCAGA  17 471 910332 N/A N/A 231406 231425 CCCATGCTGCTAGCAACTGA  28 472 910338 N/A N/A 234496 234515 AGTTATAGCGAATCAGTGGT  40 473 910344 N/A N/A 235686 235705 GCCCTATGGATAATACACCA  15 474 910350 N/A N/A 238835 238854 CTCCAGTGACATATTGCCCC  43 475 910356 N/A N/A 241826 241845 TTCGCCTTAGAGGCCTCCAG  14 476 910362 N/A N/A 245575 245594 CATACAGTTGACTAATGTAG  24 477 910368 N/A N/A 248605 248624 TCTGTTGTGCGGACATAGTA  24 478 910374 N/A N/A 251753 251772 TTTGCAGCGGAAAAGGTCTG  58 479 910380 N/A N/A 255569 255588 CAGGTCGAGGTATGGGTTAT  33 480 910386 N/A N/A 258254 258273 TAGAATGACTAATACTCTGC  24 481 910392 N/A N/A 259526 259545 GGTAAGTAGTGTAAATAGGG  14 482 260903 260922 910398 N/A N/A 261358 261377 GACTCAACCCTGGAAGGTCC  54 483

TABLE 8 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SCN2A SEQ Compound 1 Start 1 Stop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  16 227  910388 N/A N/A 259152 259171 TCTTAATGCTACCTCATAGC  68 170 260854 260873 1248329   24   43 112437 112456 GCTTTCTGTTCTGACAGTCA  70 484 1248355  372  391 168917 168936 TTGGGTCTCTTAGCTTTCTC  14 485 1248381  787  806 181698 181717 TGCAAGTATTTTAATAAGTG  37 486 1248407 1318 1337 186625 186644 ACAGATGTATCCTTCAGGAC  26 487 1248433 2329 2348 199886 199905 AACATGATAAGAACTGGACC  35 488 1248459 2539 2558 204441 204460 AAATGGGTCCATTACAACCA  58 489 1248485 3432 3451 227426 227445 GTGGTATGGTTGGAAATACA  16 490 1248511 3995 4014 243167 243186 CAGCATATTCTAACATGGTC  10 491 1248537 4540 4559 250604 250623 AATATCCATCCATCCCTTAA  60 492 1248562 6137 6156 262665 262684 GAGTTGAATTCTCATTCAGT  50 493 1248588 6872 6891 263400 263419 TGTGATTTTTTTATGTGTGA  33 494 1248614 7218 7237 263746 263765 ATAGGATATTTTTATTTTAT  79 495 1248639 7395 7414 263923 263942 ACTGGGTAAAATTACTATTT  60 496 1248665 7518 7537 264046 264065 ATAATGGAACCAATTACATC  53 497 1248689 7820 7839 264348 264367 TATTTTCTTAGAAAACTCTA  71 498 1248714 8003 8022 264531 264550 AAGCAGAAACCTACACTGCA  60 499 1248740 8353 8372 264881 264900 TTGTGAAACACAAAGTATTT  57 500 1248766 8511 8530 265039 265058 AACAATTAAATACAAAAACA  88 501 1248792 8651 8670 265179 265198 ATTAACTTCCATTCCATGAA  81 502 1248816 8756 8775 265284 265303 GTTAGTCAATTTTTTATTAA  62 503 1248842 N/A N/A 114536 114555 ATGACACATTTTAATCCCTT  63 504 1248868 N/A N/A 117743 117762 TAACAACTTAAAACTATAAA  81 505 1248894 N/A N/A 124032 124051 AACCATCACATCTTTTAGAA  72 506 1248920 N/A N/A 127323 127342 ATAAAACATACAACTACTTA  90 507 1248945 N/A N/A 128525 128544 CCATATTTTAATAATTGTTA  69 508 128568 128587 1248971 N/A N/A 141387 141406 GTATCCCATTTATTGAGTTA  76 509 1248997 N/A N/A 144994 145013 AAACTTTTTTATACTAGTTA 105 510 1249023 N/A N/A 146258 146277 CTTATTCAACTCTTTAATCA  99 511 1249049 N/A N/A 149445 149464 GCTCATATTATAAATATATT  77 512 1249075 N/A N/A 152582 152601 GTTTGTTTCCCATCCATCTA  61 513 1249101 N/A N/A 156410 156429 ACATCTCTCCTCATATTCAT  80 514 1249127 N/A N/A 162374 162393 TCTGATATTTCTATAATGTT  55 515 1249153 N/A N/A 166559 166578 TTATAATACCATATTTTTTA 113 516 1249179 N/A N/A 170517 170536 TATGTATATTTATTTTCCAA  33 517 1249205 N/A N/A 171909 171928 ATCTGATTCTCTAATCTCTG  14 518 1249231 N/A N/A 172653 172672 AATCAGTTACTAACTACAGC  31 519 1249257 N/A N/A 174419 174438 CCATTTTCCTACCATTTTCA  23 520 1249283 N/A N/A 175700 175719 CAGATACATCCCTTACCAGC  28 521 1249309 N/A N/A 176889 176908 AGAGAAATAATTATTTTCTA  82 522 1249335 N/A N/A 177800 177819 TCTCCAGTTTCATTTTCTTT  22 523 1249361 N/A N/A 178410 178429 ACATAACCATTATATACCCA  24 524 1249387 N/A N/A 179803 179822 CCTAATGTTTTTACTATAAA  62 525 1249413 N/A N/A 180553 180572 ATTTATCAACTTAAATTTTC  75 526 1249439 N/A N/A 181448 181467 ATATTGCATTTTCCACATTA  34 527 1249465 N/A N/A 183699 183718 TTAAATCATCTTAAATTAGT  92 528 1249491 N/A N/A 184369 184388 ATCTAGTTTTTATTTTTAAG  84 529 184401 184420 1249517 N/A N/A 185479 185498 AATATGCTAAATACTCCCCA  32 530 1249543 N/A N/A 186071 186090 AACTTGCTAATCTTCAGGCA  53 531 1249569 N/A N/A 188074 188093 ATTCCATTTTCACACAATAA  21 532 1249595 N/A N/A 190182 190201 CCTATGTTAAATTTGAATTA  72 533 1249621 N/A N/A 192560 192579 TTAAACCTCTTCCTTTGCCA  25 534 1249647 N/A N/A 200316 200335 AAGCAGTTAATATAATCCAA  32 535 1249673 N/A N/A 200756 200775 ATATTGATAATATTTATTAA  98 536 1249699 N/A N/A 202762 202781 AACCTTATATTTACATTGAA  53 537 1249725 N/A N/A 203198 203217 TTTCTTCTTTTTAAATCCAT  34 538 1249751 N/A N/A 203777 203796 AACAAAGTTCCATCTCTCTA  50 539 1249777 N/A N/A 205850 205869 TGAGAACCTGAATCTAGCCA  53 540 1249803 N/A N/A 207409 207428 CTAAAAATCTAAATATGTTA  96 541 1249829 N/A N/A 208944 208963 ACTCCTTTTTCAATATGTCT  35 542 1249855 N/A N/A 210467 210486 ACTAACATTTTATAAGGTAA  57 543 1249881 N/A N/A 213565 213584 TCTCTAGAAATACATACCCA  41 544 1249907 N/A N/A 216475 216494 CTATTTCCCTTAACTGCATC  48 545 1249933 N/A N/A 222131 222150 ATGAAATCAAATCTATAACA  84 546 1249959 N/A N/A 224981 225000 TACTCTATTTACAAATGTCA  62 547 1249985 N/A N/A 229139 229158 TCTGAATTTCCCATTAAACA  26 548 1250011 N/A N/A 231494 231513 AAATTATATTCTAAATACAA  80 549 1250037 N/A N/A 234138 234157 ATAACATCAATTAAATGACT  65 550 1250063 N/A N/A 235630 235649 CCATATGGATAATACACCAA  33 551 1250089 N/A N/A 237609 237628 AATATATTCTATAATTTTCT  91 552 1250115 N/A N/A 241554 241573 TGGCAATAGCGAATCAGTGT  26 553 1250141 N/A N/A 243533 243552 CTTGAGATTTTAAATATTAA  91 554 1250167 N/A N/A 246823 246842 CTTTTGTACCACCCTTCTAA  52 555 1250193 N/A N/A 250191 250210 TAATGCTTCCTTTCTACTTA  40 556 1250219 N/A N/A 253267 253286 TTAAAGATTTCCTCTTCTTA  70 557 1250245 N/A N/A 254716 254735 AATGATATCATCTCATTTAA  56 558 1250271 N/A N/A 256711 256730 GACAAACTTTTAAATTTCAC  24 559

TABLE 9 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  21 227 1248330   52   71 112465 112484 ACCACAGCATCCTCCCTCCT  87 560 1248356  373  392 168918 168937 TTTGGGTCTCTTAGCTTTCT  19 561 1248382  813  832 181724 181743 GTGAAATCTTCTAAACAAAA  27 562 1248408 1521 1540 186968 186987 AAGATCAAATTTATTAGATA  96 563 1248434 2348 2367 199905 199924 CTTCCAATAAATCCATGGAA  40 564 1248460 2541 2560 204443 204462 ACAAATGGGTCCATTACAAC  71 565 1248486 3435 3454 227429 227448 ATGGTGGTATGGTTGGAAAT  22 566 1248512 3996 4015 243168 243187 TCAGCATATTCTAACATGGT  14 567 1248538 4543 4562 250607 250626 CATAATATCCATCCATCCCT  31 568 1248563 6201 6220 262729 262748 GGTTTGGTCACACTATCATA  28 569 1248589 6945 6964 263473 263492 ACGAATAGCTATTTAAGCAC  31 570 1248615 7251 7270 263779 263798 TTTTGGTCAATTCAGGCTTC  40 571 1248640 7397 7416 263925 263944 CCACTGGGTAAAATTACTAT  52 572 1248666 7519 7538 264047 264066 TATAATGGAACCAATTACAT  58 573 1248690 7824 7843 264352 264371 TTTATATTTTCTTAGAAAAC 114 574 1248715 8021 8040 264549 264568 TTTACAGTACTAATAAAAAA  92 575 1248741 8356 8375 264884 264903 TGCTTGTGAAACACAAAGTA  43 576 1248767 8512 8531 265040 265059 CAACAATTAAATACAAAAAC  96 577 1248793 8654 8673 265182 265201 TTAATTAACTTCCATTCCAT  60 578 1248817 8757 8776 265285 265304 TGTTAGTCAATTTTTTATTA  91 579 1248843 N/A N/A 114700 114719 TTCACTTTCTCATCTTTCTT  66 580 1248869 N/A N/A 117746 117765 ACTTAACAACTTAAAACTAT  94 581 1248895 N/A N/A 124071 124090 CACTAAAACTAAAATAGTAT  91 582 1248921 N/A N/A 127328 127347 CTTAAATAAAACATACAACT  90 583 1248946 N/A N/A 128526 128545 GCCATATTTTAATAATTGTT  82 584 128569 128588 1248972 N/A N/A 141514 141533 GTATGTTTCTCCTATGCCAA  74 585 1248998 N/A N/A 145140 145159 TTTTTACTTTCAACCTGTCT  69 586 1249024 N/A N/A 146284 146303 AGAGATTTCACAACTTTCTT  67 587 1249050 N/A N/A 149569 149588 TACTTTTAAAATACAACTAA  77 588 1249076 N/A N/A 152615 152634 GGGTTACTCTAAACAGATAA  69 589 1249102 N/A N/A 156412 156431 ATACATCTCTCCTCATATTC  74 590 1249128 N/A N/A 162624 162643 GGTTTTTCTTCCATTTGTTC  71 591 1249154 N/A N/A 166705 166724 CTCATGCTTTTTATTTGCTA  75 592 1249180 N/A N/A 170593 170612 CTCAAAGCTTTTAAATGCTA  38 593 1249206 N/A N/A 171947 171966 TTCTGATCCATTCAAACTTA  31 594 1249232 N/A N/A 172760 172779 CCAAGCATTTTTAACTTACA  20 595 1249258 N/A N/A 174424 174443 GTTTTCCATTTTCCTACCAT  14 596 1249284 N/A N/A 175786 175805 TGGATCATCATAACACTGGC  19 597 1249310 N/A N/A 176892 176911 ACAAGAGAAATAATTATTTT  90 598 1249336 N/A N/A 177878 177897 CTTTCTATTACTCTTAGGAT  19 599 1249362 N/A N/A 178414 178433 ACAAACATAACCATTATATA  95 600 1249388 N/A N/A 179813 179832 TTTTCTCACTCCTAATGTTT  44 601 1249414 N/A N/A 180595 180614 TTAAAAAGATTAAATGCAAA  90 602 1249440 N/A N/A 181595 181614 GTACATATCTTAAAGATGAC  46 603 1249466 N/A N/A 183701 183720 TATTAAATCATCTTAAATTA  89 604 1249492 N/A N/A 184370 184389 TATCTAGTTTTTATTTTTAA  71 605 184402 184421 1249518 N/A N/A 185489 185508 ACTTTGCTAAAATATGCTAA  50 606 1249544 N/A N/A 186082 186101 GCAAGTTACTTAACTTGCTA  81 607 1249570 N/A N/A 188176 188195 AAGATCATAATAACATGTTC  70 608 1249596 N/A N/A 190485 190504 ATTTAGGCAAATTTTGGCCA  82 609 1249622 N/A N/A 192836 192855 CCCAGATCTCATCTTGAGTT  28 610 194791 194810 1249648 N/A N/A 200370 200389 ACATTTTTAATTTATATTTC  94 611 1249674 N/A N/A 201016 201035 CTTTCATTCTCCTTTTCTCT  38 612 1249700 N/A N/A 202776 202795 CTAAACTCCCAAATAACCTT  39 613 1249726 N/A N/A 203264 203283 GTACACCCTATTACCTGTTC  19 614 1249752 N/A N/A 203825 203844 AAGTCTCAAATTAAATTTTA  72 615 1249778 N/A N/A 206284 206303 TACAGATCCTACATTCCTTA  54 616 1249804 N/A N/A 207846 207865 ATAGGATTTTCTAAATACAA  48 617 1249830 N/A N/A 209008 209027 CCTTTCCCCTAAAATTAGCC  36 618 1249856 N/A N/A 210650 210669 TTCTTTATTTTATCTGGCCA  44 619 1249882 N/A N/A 213610 213629 GTTCATATTTCAAAATCTAT  26 620 1249908 N/A N/A 216476 216495 CCTATTTCCCTTAACTGCAT  53 621 1249934 N/A N/A 222168 222187 CTTCTTCCAACATATACCAA  42 622 1249960 N/A N/A 225049 225068 TCTTGATACACATCCATCAA  51 623 1249986 N/A N/A 229172 229191 CTGTTATTTATACCTTCCTA  59 624 1250012 N/A N/A 231744 231763 ATGATAAATTTAAATAATAT  70 625 1250038 N/A N/A 234144 234163 TTCTTGATAACATCAATTAA  65 626 1250064 N/A N/A 235632 235651 GGCCATATGGATAATACACC  24 627 1250090 N/A N/A 237618 237637 TTGTTATTAAATATATTCTA  88 628 1250116 N/A N/A 241555 241574 TTGGCAATAGCGAATCAGTG  27 629 1250142 N/A N/A 243534 243553 ACTTGAGATTTTAAATATTA  71 630 1250168 N/A N/A 246959 246978 ATCATTTTTTTAAAATCCTC  36 631 1250194 N/A N/A 250202 250221 ATTATTTATCTTAATGCTTC  31 632 1250220 N/A N/A 253310 253329 TGCACTTTCCTTTCTAAGCA  33 633 1250246 N/A N/A 254960 254979 CGGTCTGTTTTATATTGTCA  20 634 1250272 N/A N/A 256712 256731 AGACAAACTTTTAAATTTCA  55 635 1250297 N/A N/A 259160 259179 ATCTTATCTCTTAATGCTAC  79 636

TABLE 10 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  16 227 1248331   92  111 112505 112524 GCTCTATCCTCATTAAAGAA  63 637 1248357  375  394 168920 168939 TGTTTGGGTCTCTTAGCTTT  18 638 1248383  814  833 181725 181744 TGTGAAATCTTCTAAACAAA  53 639 1248409 1605 1624 187052 187071 ATCTGCTGAAATTCAGCTTC  44 640 1248435 2352 2371 199909 199928 GGATCTTCCAATAAATCCAT  42 641 1248461 2604 2623 204506 204525 GGATAGTGCTCCATAGCCAT  11 642 1248487 3516 3535 227510 227529 ACATATTTTTCTACACTGCT  15 643 1248513 3999 4018 243171 243190 TTGTCAGCATATTCTAACAT  39 644 1248539 4544 4563 250608 250627 ACATAATATCCATCCATCCC  39 645 1248564 6226 6245 262754 262773 GTCTTTTTCAAATTTTTCTT  39 646 1248590 6960 6979 263488 263507 AGACACCTTAAAAATACGAA  41 647 1248616 7253 7272 263781 263800 TTTTTTGGTCAATTCAGGCT  27 648 1248641 7414 7433 263942 263961 GTTTGCTCAAACATGCACCA  52 649 1248667 7526 7545 264054 264073 TTCAAACTATAATGGAACCA  39 650 1248691 7827 7846 264355 264374 GTATTTATATTTTCTTAGAA  79 651 1248716 8022 8041 264550 264569 GTTTACAGTACTAATAAAAA  77 652 1248742 8375 8394 264903 264922 AAGAATCTACATTTATTGTT  64 653 1248768 8513 8532 265041 265060 ACAACAATTAAATACAAAAA  77 654 1248794 8655 8674 265183 265202 CTTAATTAACTTCCATTCCA  59 655 1248818 N/A N/A 166899 166918 GGCATTATTGTAACTACCAC  68 656 1248844 N/A N/A 114822 114841 ATCCTCCTAAAATCTTTTCC  74 657 1248870 N/A N/A 117753 117772 GCAAAAGACTTAACAACTTA  60 658 1248896 N/A N/A 124079 124098 AACATTGTCACTAAAACTAA  71 659 1248922 N/A N/A 127515 127534 ATATTGATATTATCTAGAAA 106 660 1248947 N/A N/A 128527 128546 AGCCATATTTTAATAATTGT  56 661 128570 128589 1248973 N/A N/A 141858 141877 TTTTACTCAACCTAATGTCC  88 662 1248999 N/A N/A 145147 145166 ACTGATTTTTTTACTTTCAA  82 663 1249025 N/A N/A 146336 146355 TAAGGATTAAACTAAAATCA  96 664 1249051 N/A N/A 149572 149591 GCTTACTTTTAAAATACAAC  76 665 1249077 N/A N/A 152630 152649 TTATTATAATTAACTGGGTT 101 666 1249103 N/A N/A 156668 156687 TGGATCCCTTTCTATACCTA  77 667 1249129 N/A N/A 162671 162690 AGTCTGTTTCTCATTTCCCA  65 668 1249155 N/A N/A 167626 167645 CTTTTCAAAAAATCAATCTA  76 669 1249181 N/A N/A 170745 170764 ACTTCAATAAAACATAGGAA  38 670 1249207 N/A N/A 171986 172005 CTCCATCTCATCATTCAGAT  19 671 1249233 N/A N/A 172820 172839 CTAGTGGTAATAAATATACA  35 672 1249259 N/A N/A 174427 174446 TATGTTTTCCATTTTCCTAC  39 673 1249285 N/A N/A 175789 175808 GCCTGGATCATCATAACACT  22 674 1249311 N/A N/A 176908 176927 ATATATTTCAACATTAACAA  59 675 1249337 N/A N/A 177882 177901 GTAGCTTTCTATTACTCTTA   9 676 1249363 N/A N/A 178420 178439 TGCTCAACAAACATAACCAT  41 677 1249389 N/A N/A 179820 179839 TCATATCTTTTCTCACTCCT  38 678 1249415 N/A N/A 180640 180659 GCCAAGCCATCAACTATTTT  35 679 1249441 N/A N/A 181611 181630 AGTGGTTAATTTACAAGTAC  55 680 1249467 N/A N/A 183705 183724 TATGTATTAAATCATCTTAA  50 681 1249493 N/A N/A 184519 184538 ATTTATTCCCTCTTATGATA  53 682 1249519 N/A N/A 185499 185518 GTTTGTAACCACTTTGCTAA  36 683 1249545 N/A N/A 186349 186368 AAGCAATCATATCATGATTA  37 684 1249571 N/A N/A 188217 188236 CTATGATATCTAATTATCTA  61 685 1249597 N/A N/A 190580 190599 TAGTTTTATTCAATTAGAAA  82 686 1249623 N/A N/A 192837 192856 ACCCAGATCTCATCTTGAGT  37 687 194792 194811 1249649 N/A N/A 200374 200393 ATTCACATTTTTAATTTATA  82 688 1249675 N/A N/A 201589 201608 AGTAATGTCTTATTTAGCTC  17 689 1249701 N/A N/A 202784 202803 AAATACTTCTAAACTCCCAA  40 690 1249727 N/A N/A 203333 203352 ATAATCTCTTCATCAACTTA  56 691 1249753 N/A N/A 203874 203893 GTGATCTTCTAATTAGATAA  25 692 1249779 N/A N/A 206308 206327 TACTATTCCATAATTCACCT  45 693 1249805 N/A N/A 207897 207916 GCAATCTTATTTATTAGTTC  24 694 1249831 N/A N/A 209009 209028 GCCTTTCCCCTAAAATTAGC  28 695 1249857 N/A N/A 210729 210748 TTTGTTTATCTTAAAATTCT  49 696 1249883 N/A N/A 213626 213645 TTACATTTTTATAATAGTTC  82 697 1249909 N/A N/A 216559 216578 ACCAAAGTATTTAATTTATT  84 698 1249935 N/A N/A 222169 222188 TCTTCTTCCAACATATACCA  42 699 1249961 N/A N/A 225181 225200 TGGATTAAAAAAACAGACAA  57 700 1249987 N/A N/A 229264 229283 ATTAAAGTAATTCTTTGCCC  26 701 1250013 N/A N/A 231745 231764 CATGATAAATTTAAATAATA  95 702 1250039 N/A N/A 234163 234182 ATTCTGATTTATAAAACCCT  30 703 1250065 N/A N/A 235633 235652 AGGCCATATGGATAATACAC  21 704 1250091 N/A N/A 237640 237659 TGACATGAAAACATATACCA  56 705 1250117 N/A N/A 241556 241575 GTTGGCAATAGCGAATCAGT  22 706 1250143 N/A N/A 243555 243574 ATTCATATTTTATTTTGCAT  40 707 1250169 N/A N/A 246960 246979 TATCATTTTTTTAAAATCCT  78 708 1250195 N/A N/A 250330 250349 ATGCTATCATAAAAACAATA  40 709 1250221 N/A N/A 253346 253365 TAGACAATTTCACCCAACAA  91 710 1250247 N/A N/A 255011 255030 TATCCATTTTCTTTGAGTTA  61 711 1250273 N/A N/A 256737 256756 TCTTTAGTTCCCATATTCAA  60 712 1250298 N/A N/A 259161 259180 AATCTTATCTCTTAATGCTA  70 713

TABLE 11 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5' to 3') (% control) NO  910059 7528 7547 264056 264075 GCTTCAAACTATAATGGAAC  35 193  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  18 227 1248332   96  115 112509 112528 ATGTGCTCTATCCTCATTAA  70 714 1248358  376  395 168921 168940 CTGTTTGGGTCTCTTAGCTT  24 715 1248384  815  834 181726 181745 ATGTGAAATCTTCTAAACAA  60 716 1248410 1608 1627 187055 187074 AGCATCTGCTGAAATTCAGC  32 717 1248436 2353 2372 199910 199929 AGGATCTTCCAATAAATCCA  46 718 1248462 2605 2624 204507 204526 GGGATAGTGCTCCATAGCCA  12 719 1248488 3517 3536 227511 227530 GACATATTTTTCTACACTGC  25 720 1248514 4002 4021 243174 243193 ACCTTGTCAGCATATTCTAA  44 721 1248540 4545 4564 250609 250628 TACATAATATCCATCCATCC  49 722 1248565 6230 6249 262758 262777 ATTTGTCTTTTTCAAATTTT  88 723 1248591 6984 7003 263512 263531 GGCACATTAAATTTTTTCTG  57 724 1248617 7282 7301 263810 263829 ATCAACTTTATAAAGTGGTG  35 725 1248642 7417 7436 263945 263964 TTTGTTTGCTCAAACATGCA  70 726 1248692 7830 7849 264358 264377 ACAGTATTTATATTTTCTTA  46 727 1248717 8028 8047 264556 264575 GTGCAAGTTTACAGTACTAA  25 728 1248743 8376 8395 264904 264923 AAAGAATCTACATTTATTGT  78 729 1248769 8515 8534 265043 265062 AGACAACAATTAAATACAAA  77 730 1248795 8656 8675 265184 265203 TCTTAATTAACTTCCATTCC  75 731 1248819 V/A N/A 166998 167017 TTTTTTTAATTCTCCTTCAA  76 732 1248845 N/A N/A 114826 114845 TCACATCCTCCTAAAATCTT  92 733 1248871 N/A N/A 117846 117865 ACACAATCACATAATTGTAT  64 734 1248897 N/A N/A 124805 124824 ATTATATTAATCAAAGTCTT  69 735 1248923 N/A N/A 127539 127558 GAGTTTTTATTTTCTAGCAA  78 736 1248948 N/A N/A 128528 128547 GAGCCATATTTTAATAATTG  63 737 128571 128590 1248974 N/A N/A 141865 141884 TGGCTTATTTTACTCAACCT  64 738 1249000 N/A N/A 145209 145228 TTTTGATATTCATATAGCCA 101 739 1249026 N/A N/A 146347 146366 CTTATATTCATTAAGGATTA  71 740 1249052 N/A 149573 149592 GGCTTACTTTTAAAATACAA  82 741 1249078 N/A N/A 152644 152663 GCAGATTCAATATTTTATTA  76 742 1249104 N/A N/A 156786 156805 CTGATTTCAAATACTAAATA  74 743 1249130 N/A N/A 162724 162743 TTTTTTCACATCAAAGATAC  94 744 1249156 N/A N/A 167638 167657 TATTTTTTCCATCTTTTCAA  58 745 1249182 N/A N/A 170920 170939 ACTACTCTATTTAATTTCAA  66 746 1249208 N/A N/A 171999 172018 TGGGTTTTCTTAACTCCATC  27 747 1249234 N/A N/A 172873 172892 AAGTTTAAAATAAAAACTTA  82 748 1249260 N/A N/A 174428 174447 CTATGTTTTCCATTTTCCTA  44 749 1249286 N/A N/A 175950 175969 CTATTAATTTCTTTATGCCA  20 750 1249312 V/A N/A 176946 176965 ATAGTGGTATAATTTAGTTA  32 751 1249338 N/A N/A 177884 177903 TGGTAGCTTTCTATTACTCT  13 752 1249364 N/A N/A 178424 178443 ACATTGCTCAACAAACATAA  61 753 1249390 N/A N/A 179827 179846 GTGCTCTTCATATCTTTTCT   9 754 1249416 N/A N/A 180670 180689 AGCAACCTCATATTTAGATC  12 755 1249442 N/A N/A 181630 181649 AAGCTCACATTAAAAATCTA  89 756 1249468 N/A N/A 183768 183787 CTTTTACTATATCAATGGAC  29 757 1249494 N/A N/A 184520 184539 TATTTATTCCCTCTTATGAT  73 758 1249520 N/A N/A 185598 185617 ATTATTATACCCATTTGTCA  46 759 1249546 N/A N/A 186363 186382 ATGTCTCCATATAAAAGCAA  45 760 1249572 N/A N/A 188762 188781 TTCATGTAATTTAATATTTT  77 761 1249598 N/A N/A 190665 190684 GAGAATATCATATCTATGAA  21 762 1249624 N/A N/A 194838 194857 ATCTAGGTTTTTATATGCCT  55 763 1249650 N/A N/A 200387 200406 ATATCAAACCCTAATTCACA  68 764 1249676 N/A N/A 201648 201667 TGAACTCCAAATCTTAATTA  38 765 1249702 V/A N/A 202810 202829 TAGTTATTATGCACTAGTTA  39 766 1249728 N/A N/A 203338 203357 GCAAGATAATCTCTTCATCA  22 767 1249754 N/A N/A 203875 203894 GGTGATCTTCTAATTAGATA  23 768 1249780 N/A N/A 206311 206330 TTCTACTATTCCATAATTCA  64 769 1249806 N/A N/A 207901 207920 TTCTGCAATCTTATTTATTA  39 770 1249832 N/A N/A 209105 209124 TTTTTCCACATCCTTGATAA  56 771 1249858 N/A N/A 210809 210828 ATATTTTTCCTATTCGGCCT  48 772 1249884 N/A N/A 213650 213669 CTTTAGTTTTCCTTTTATAA  62 773 1249910 N/A N/A 216608 216627 AGTGCATTATTTAATGGCAT  64 774 1249936 N/A N/A 222244 222263 TTATATTTCTTAATTCCCCA  47 775 1249962 N/A N/A 225297 225316 GTCAGTCTCTATACTATGAC  60 776 1249988 N/A N/A 229313 229332 ATTCAACTTTCAAACAATAA  56 777 1250014 N/A N/A 231811 231830 CTTCATTTTAAAAACACCCT  52 778 1250040 N/A N/A 234397 234416 TTTATCAATTTAAAACATTT  74 779 1250066 N/A N/A 235634 235653 TAGGCCATATGGATAATACA  35 780 1250092 N/A N/A 237671 237690 CAGCAACCATCTAAATTTAT  44 781 1250118 N/A N/A 241558 241577 TGGTTGGCAATAGCGAATCA  54 782 1250144 N/A N/A 243569 243588 AGCAAAATTTCTAAATTCAT  67 783 1250170 N/A N/A 246986 247005 AACTTATTTTCAAATATCAC  56 784 1250196 N/A N/A 250400 250419 TTATATTCCTCTATAACATC  61 785 1250222 N/A N/A 253512 253531 AGTGAGTTTTTAATTATCTA  40 786 1250248 N/A N/A 255029 255048 TGTTTGACCCAATATAGCTA  43 787 1250274 N/A N/A 256849 256868 TAGCATCTCCAATTTTCTCA  50 788 1250299 N/A N/A 259495 259514 CAGATCTCAAATCTTATCTC  39 789

TABLE 12 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  23 227 1248333   97  116 112510 112529 CATGTGCTCTATCCTCATTA  57 790 1248359  377  396 168922 168941 CCTGTTTGGGTCTCTTAGCT  25 791 1248385  946  965 182414 182433 TGAAATTGTTTTCAATGCTC  17 792 1248411 1630 1649 187077 187096 TTGTTGCTTTTTCAACTGTT  58 793 1248437 2354 2373 199911 199930 TAGGATCTTCCAATAAATCC  47 794 1248463 2646 2665 204548 204567 AGGTTTCCAACAGACAGTAC  56 795 1248489 3535 3554 227529 227548 GTAATCACTTTCATCCACGA  18 796 1248515 4013 4032 243185 243204 TGTAAGTGAAAACCTTGTCA  32 797 1248541 4547 4566 250611 250630 CATACATAATATCCATCCAT  38 798 1248566 6248 6267 262776 262795 CTTTGTCTTCCTTTTCTGAT  57 799 1248592 6998 7017 263526 263545 ATGGAACATTTACAGGCACA  32 800 1248618 7283 7302 263811 263830 AATCAACTTTATAAAGTGGT  49 801 1248643 7418 7437 263946 263965 TTTTGTTTGCTCAAACATGC  74 802 1248668 7529 7548 264057 264076 AGCTTCAAACTATAATGGAA  28 803 1248693 7832 7851 264360 264379 TTACAGTATTTATATTTTCT  71 804 1248718 8029 8048 264557 264576 TGTGCAAGTTTACAGTACTA  26 805 1248744 8379 8398 264907 264926 TATAAAGAATCTACATTTAT 100 806 1248770 8516 8535 265044 265063 AAGACAACAATTAAATACAA  69 807 1248796 8659 8678 265187 265206 TCTTCTTAATTAACTTCCAT  71 808 1248820 N/A N/A 166999 167018 TTTTTTTTAATTCTCCTTCA 106 809 1248846 N/A N/A 114827 114846 GTCACATCCTCCTAAAATCT  67 810 1248872 N/A N/A 117883 117902 ATACATATCACACAACACAA  72 811 1248898 N/A N/A 124812 124831 GTTAGCTATTATATTAATCA  60 812 1248924 N/A N/A 127954 127973 ATATCAACAAATACAAACAA  81 813 1248949 N/A N/A 128769 128788 ACTGAAATTATCATTATTAC  70 814 1248975 N/A N/A 141917 141936 TTTTTAGATTCCATACCTAA  70 815 1249001 N/A N/A 145228 145247 TTTGTCTTAAAATCTACTTT  74 816 1249027 N/A N/A 146354 146373 CAGGCTTCTTATATTCATTA  68 817 1249053 N/A N/A 149574 149593 TGGCTTACTTTTAAAATACA  76 818 1249079 N/A N/A 152647 152666 CATGCAGATTCAATATTTTA  93 819 1249105 N/A N/A 156789 156808 TGTCTGATTTCAAATACTAA  79 820 1249131 N/A N/A 162726 162745 TATTTTTTCACATCAAAGAT  89 821 1249157 N/A N/A 167676 167695 ATACAATCAACATCTTGACT  56 822 1249183 N/A N/A 170921 170940 AACTACTCTATTTAATTTCA  71 823 1249209 N/A N/A 172046 172065 ACAAAAGTTTTAAAACAAAA  85 824 1249235 N/A N/A 172947 172966 ACAATAGCTCCTAATAGATA  58 825 1249261 N/A N/A 174429 174448 CCTATGTTTTCCATTTTCCT  34 826 1249287 N/A N/A 175957 175976 TTTTAATCTATTAATTTCTT  86 827 1249313 N/A N/A 176957 176976 ACTTACTCTTTATAGTGGTA  11 828 1249339 N/A N/A 177944 177963 ATTTAATCCATTCTGCATAC  46 829 1249365 N/A N/A 178434 178453 CCATCAACAAACATTGCTCA  43 830 1249391 N/A N/A 179935 179954 TCATATTTAATAAAAAGCAT  78 831 1249417 N/A N/A 180686 180705 GCCATTTCTATAACTCAGCA   8 832 1249443 N/A N/A 181633 181652 GCCAAGCTCACATTAAAAAT  46 833 1249469 N/A N/A 183769 183788 ACTTTTACTATATCAATGGA  42 834 1249495 N/A N/A 184524 184543 TAGGTATTTATTCCCTCTTA  17 835 1249521 N/A N/A 185614 185633 TCATCACAAAAACCCTATTA  54 836 1249547 N/A N/A 186364 186383 TATGTCTCCATATAAAAGCA  58 837 1249573 N/A N/A 189437 189456 TCTAAATTTTAAAATTTCAA  79 838 1249599 N/A N/A 190734 190753 GTGATTGCTTATAATACCCA  21 839 1249625 N/A N/A 194853 194872 TTTATACCTACTAATATCTA  75 840 1249651 N/A N/A 200390 200409 TTAATATCAAACCCTAATTC  71 841 1249677 N/A N/A 201663 201682 TGGGTGCATTTATTTTGAAC  23 842 1249703 N/A N/A 202851 202870 AAACAATAAATAATATTTGA  78 843 1249729 N/A N/A 203339 203358 GGCAAGATAATCTCTTCATC  14 844 1249755 N/A N/A 203876 203895 TGGTGATCTTCTAATTAGAT  22 845 1249781 N/A N/A 206319 206338 TATGGATTTTCTACTATTCC  58 846 1249807 N/A N/A 207983 208002 ATAGAATTTTCCTAATTTTA  76 847 1249833 N/A N/A 209119 209138 CATAACCATTCTAATTTTTC  53 848 1249859 N/A N/A 210859 210878 CATTTATTCATATCTAGTGA  60 849 1249885 N/A N/A 213718 213737 TTTTCTTCCTCTAACAAATC  77 850 1249911 N/A N/A 216782 216801 TTCTTTTTAACCTTTATATC  71 851 1249937 N/A N/A 222245 222264 CTTATATTTCTTAATTCCCC  77 852 1249963 N/A N/A 225443 225462 TCATGCTTCTATCATGCTAA  24 853 1249989 N/A N/A 229453 229472 TTCTATTTTATAAATGCCGA  27 854 1250015 N/A N/A 231813 231832 CTCTTCATTTTAAAAACACC  25 855 1250041 N/A N/A 234398 234417 GTTTATCAATTTAAAACATT  81 856 1250067 N/A N/A 235636 235655 TCTAGGCCATATGGATAATA  37 857 1250093 N/A N/A 237672 237691 ACAGCAACCATCTAAATTTA  71 858 1250119 N/A N/A 241579 241598 TCTACTTCTTATCATTCACT  20 859 1250145 N/A N/A 243715 243734 TTTGGACTTTCAAATTTCTT  40 860 1250171 N/A N/A 246987 247006 CAACTTATTTTCAAATATCA  56 861 1250197 N/A N/A 250401 250420 TTTATATTCCTCTATAACAT  36 862 1250223 N/A N/A 253875 253894 ATCTGAATTATTAATTGCTT  40 863 1250249 N/A N/A 255071 255090 GTATTATTTCCTAAAGACTA  73 864 1250275 N/A N/A 256949 256968 AAGAAACCTTTATTTTGCTA  78 865 1250300 N/A N/A 259521 259540 GTAGTGTAAATAGGGAAGCT  31 866 260898 260917

TABLE 13 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  15 227 1248334   99  118 112512 112531 CACATGTGCTCTATCCTCAT  59 867 1248360  379  398 168924 168943 TTCCTGTTTGGGTCTCTTAG  29 868 1248386 1007 1026 183354 183373 CAGAAAGCTTCTTCACTGAC  48 869 1248412 1711 1730 188520 188539 TGAAAAAACTCCTATCCCAC  39 870 1248438 2355 2374 199912 199931 GTAGGATCTTCCAATAAATC  28 871 1248464 2719 2738 215348 215367 TTGAAAGTAATAATATGGAT  77 872 1248490 3678 3697 238143 238162 GAACTAGTTGCATTTAGCTT  25 873 1248516 4033 4052 243205 243224 CAGCATTTCCAGAATGAATA  32 874 1248542 4597 4616 253602 253621 GTTGTCTTCATACTTGGGTT  24 875 1248567 6249 6268 262777 262796 CCTTTGTCTTCCTTTTCTGA  45 876 1248593 7010 7029 263538 263557 GCTTGTGATTCTATGGAACA  19 877 1248619 7288 7307 263816 263835 AGCAGAATCAACTTTATAAA  52 878 1248644 7430 7449 263958 263977 TTAAATCATCATTTTTGTTT  81 879 1248669 7530 7549 264058 264077 CAGCTTCAAACTATAATGGA  34 880 1248694 7833 7852 264361 264380 TTTACAGTATTTATATTTTC  71 881 1248719 8092 8111 264620 264639 GGCATTACTATTGAAAGCAA  51 882 1248745 8380 8399 264908 264927 GTATAAAGAATCTACATTTA  73 883 1248771 8518 8537 265046 265065 CAAAGACAACAATTAAATAC  73 884 1248797 8660 8679 265188 265207 CTCTTCTTAATTAACTTCCA  45 885 1248821 N/A N/A 112682 112701 GTCATTCTTAACATAGATAA  61 886 1248847 N/A N/A 114843 114862 AAGATCTAATTTAACTGTCA  61 887 1248873 N/A N/A 117895 117914 TGTCATTTCCCCATACATAT  79 888 1248899 N/A N/A 124922 124941 AAATTTAGTCATAATAGTAC  79 889 1248925 N/A N/A 127957 127976 AATATATCAACAAATACAAA  86 890 1248950 N/A N/A 129692 129711 GAGGACACTTTAATTATGAA  61 891 1248976 N/A N/A 141941 141960 CTTTCTGTTTCTGTGAGTTT  23 892 249003 249022 1249002 N/A N/A 145254 145273 GACCATTTTTATCTGTGTTA  76 893 1249028 N/A N/A 146355 146374 TCAGGCTTCTTATATTCATT  57 894 1249054 N/A N/A 150098 150117 ACATTATCTTTTACTAAGTA  75 895 1249080 N/A N/A 152667 152686 CCTTCTCATTCCATTGCCAA  72 896 1249106 N/A N/A 157633 157652 TTCTTCTTTTCATCAAAGAC  57 897 1249132 N/A N/A 162865 162884 CCTTAACATTATATTAGTTA  70 898 1249158 N/A N/A 167737 167756 ATCAGTCATTCCAAATGTTA  39 899 1249184 N/A N/A 170939 170958 ATAAAATCTCTCATTTCCAA  52 900 1249210 N/A N/A 172185 172204 CAGAATTTCTTAAACTGCCC  21 901 1249236 N/A N/A 172956 172975 ATTTGATACACAATAGCTCC  26 902 1249262 N/A N/A 174579 174598 TTTATCATTATTAATGTCTA  48 903 1249288 N/A N/A 175963 175982 GATGTTTTTTAATCTATTAA  62 904 1249314 N/A N/A 176965 176984 ACTTAAAAACTTACTCTTTA  49 905 1249340 N/A N/A 177947 177966 TCCATTTAATCCATTCTGCA  23 906 1249366 N/A N/A 178461 178480 CTTCTACTCTCCTCATCCTA  43 907 1249392 N/A N/A 179936 179955 TTCATATTTAATAAAAAGCA  64 908 1249418 N/A N/A 180689 180708 TTTGCCATTTCTATAACTCA  14 909 1249444 N/A N/A 181938 181957 TGATAGTTCCTAATTTCTCC  17 910 1249470 N/A N/A 183774 183793 TGAGAACTTTTACTATATCA  18 911 1249496 N/A N/A 184558 184577 CAATTTTAACTTAATTTCCT  53 912 1249522 N/A N/A 185619 185638 CTTCATCATCACAAAAACCC  47 913 1249548 N/A N/A 186387 186406 ATAATTGTCATTATTATATT  70 914 1249574 N/A N/A 189438 189457 TTCTAAATTTTAAAATTTCA  91 915 1249600 N/A N/A 190808 190827 ACTCTATTTTTATATAGAGA  76 916 1249626 N/A N/A 194860 194879 CCATTATTTTATACCTACTA  33 917 1249652 N/A N/A 200393 200412 AAGTTAATATCAAACCCTAA  58 918 1249678 N/A N/A 201716 201735 CATCCTTTCCATCCTAAGCA  48 919 1249704 N/A N/A 202855 202874 TTGTAAACAATAAATAATAT 101 920 1249730 N/A N/A 203354 203373 CTACCATCTTCCTTTGGCAA  33 921 1249756 N/A N/A 203930 203949 CTAAGAACCTTAATCAGTCA  45 922 1249782 N/A N/A 206363 206382 TAGGGAATATCCTATAGGCA  32 923 1249808 N/A N/A 208114 208133 AATGTGCTTTCATTTATTTA  35 924 1249834 N/A N/A 209260 209279 GTTTTTAATTCTCTTAGATA  27 925 1249860 N/A N/A 210869 210888 TATTTACCCACATTTATTCA  65 926 1249886 N/A N/A 213719 213738 ATTTTCTTCCTCTAACAAAT  71 927 1249912 N/A N/A 216786 216805 AGGCTTCTTTTTAACCTTTA  22 928 1249938 N/A N/A 222278 222297 CATAAATTAAATTCTACCCA  70 929 1249964 N/A N/A 225468 225487 AGGATTCTACATTCTTGCTA  54 930 1249990 N/A N/A 229454 229473 ATTCTATTTTATAAATGCCG  23 931 1250016 N/A N/A 231814 231833 TCTCTTCATTTTAAAAACAC  43 932 1250042 N/A N/A 234546 234565 ATCCAGTATTTATTTAGAGA  28 933 1250068 N/A N/A 235802 235821 GCTTATCACACATCTTGAAC  34 934 1250094 N/A N/A 237763 237782 GTTTTATTCTAAAATTGTGA  46 935 1250120 N/A N/A 241580 241599 GTCTACTTCTTATCATTCAC  27 936 1250146 N/A N/A 243755 243774 TTGCTTCTATATCATACAAA  10 937 1250172 N/A N/A 247052 247071 AGTAACTATTTTCTTAGTTA  33 938 1250198 N/A N/A 250409 250428 ACTTCAAATTTATATTCCTC  16 939 1250224 N/A N/A 253927 253946 AAATTATGCCATATTAGTCA  27 940 1250250 N/A N/A 255087 255106 TCTATTCATTCAAATTGTAT  70 941 1250276 N/A N/A 256995 257014 CTCTAAAATTCCTTTTGCTT  55 942 1250301 N/A N/A 259522 259541 AGTAGTGTAAATAGGGAAGC  33 943 260899 260918

TABLE 14 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910023 4598 4617 253603 253622 GGTTGTCTTCATACTTGGGT  19  109  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  23  227 1248335  108  127 112521 112540 GTAAAATCTCACATGTGCTC  59  944 1248361  402  421 168947 168966 TTTTCATCATCCTCATCCTT  48  945 1248387 1039 1058 183386 183405 GCTTAGACAGAACACAGTCA  38  946 1248413 1712 1731 188521 188540 CTGAAAAAACTCCTATCCCA  48  947 1248439 2384 2403 199941 199960 TGGCTATACTCATTGCTCTT  20  948 1248465 2762 2781 215391 215410 AACTAAGGCTCACAATAAAA  54  949 1248491 3711 3730 238176 238195 GGAGCTCCAATATCAACCGT  45  950 1248517 4034 4053 243206 243225 GCAGCATTTCCAGAATGAAT  25  951 1248568 6260 6279 262788 262807 TGATATCTTTCCCTTTGTCT  57  952 1248594 7025 7044 263553 263572 AAACAACTCTTTAATGCTTG  51  953 1248620 7298 7317 263826 263845 TGCAGGATAAAGCAGAATCA  42  954 1248645 7431 7450 263959 263978 CTTAAATCATCATTTTTGTT  88  955 1248670 7534 7553 264062 264081 GTGACAGCTTCAAACTATAA  64  956 1248695 7842 7861 264370 264389 AATGAACTTTTTACAGTATT  60  957 1248720 8101 8120 264629 264648 CAATGATAAGGCATTACTAT  69  958 1248746 8382 8401 264910 264929 CAGTATAAAGAATCTACATT  69  959 1248772 8529 8548 265057 265076 AAAGATAGAAACAAAGACAA  82  960 1248798 8661 8680 265189 265208 ACTCTTCTTAATTAACTTCC  53  961 1248822 N/A N/A 112684 112703 ATGTCATTCTTAACATAGAT  68  962 1248848 N/A N/A 114869 114888 CTTTATTTATATCCAACTCA  84  963 1248874 N/A N/A 118831 118850 GGCAACAAAATCATGAACAA  57  964 1248900 N/A N/A 124931 124950 TTATATTTTAAATTTAGTCA  73  965 1248926 N/A N/A 128080 128099 TGGTTAATTTATAATTAACC  88  966 1248951 N/A N/A 131500 131519 CTGTTTTCCATAATTGCTGA  63  967 1248977 N/A N/A 142005 142024 CCAACATTTTCCATTCCTCC 110  968 1249003 N/A N/A 145369 145388 CTTTTTACTTTATTCTGCCA  86  969 1249029 N/A N/A 146372 146391 CCCAAGAGATCATTTAGTCA  65  970 1249055 N/A N/A 150101 150120 ATTACATTATCTTTTACTAA  88  971 1249081 N/A N/A 153912 153931 AACTTATTAATAATTATTTA  95  972 1249107 N/A N/A 157753 157772 ATTCTGGATTTTAATAATCA 101  973 1249133 N/A N/A 162869 162888 GTTTCCTTAACATTATATTA  75  974 1249159 N/A N/A 167780 167799 AATCATATTTCACCAGACTA  44  975 1249185 N/A N/A 171260 171279 TTCAAATATTTTCTAGGCCT  26  976 1249211 N/A N/A 172186 172205 TCAGAATTTCTTAAACTGCC  36  977 1249237 N/A N/A 172998 173017 CATAATTTCTCATTCAGCCA  14  978 1249263 N/A N/A 174585 174604 ATACATTTTATCATTATTAA  86  979 1249289 N/A N/A 175992 176011 ATAAACCTTTTATAATATCA  72  980 1249315 N/A N/A 176968 176987 GACACTTAAAAACTTACTCT  21  981 1249341 N/A N/A 177954 177973 GTTTGGCTCCATTTAATCCA  12  982 1249367 N/A N/A 178471 178490 ATCTACCTCTCTTCTACTCT  59  983 1249393 N/A N/A 179939 179958 ACTTTCATATTTAATAAAAA  72  984 1249419 N/A N/A 180715 180734 TTATTATTCTATTATTGACC  55  985 1249445 N/A N/A 181954 181973 GCCATGTAATTTACTATGAT  20  986 1249471 N/A N/A 183775 183794 ATGAGAACTTTTACTATATC  37  987 1249497 N/A N/A 184633 184652 TTTCATGCAAATAAATTTTA  80  988 1249523 N/A N/A 185621 185640 CACTTCATCATCACAAAAAC  58  989 1249549 N/A N/A 186396 186415 CTGTGATTCATAATTGTCAT  35  990 1249575 N/A N/A 189605 189624 ATATTGCAAATAACAACACA  59  991 1249601 N/A N/A 190841 190860 ACTATTTCTTTATCAAGCAA  30  992 1249627 N/A N/A 194862 194881 AACCATTATTTTATACCTAC  43  993 1249653 N/A N/A 200422 200441 TACAAAATTTTAAACACTTT 107  994 1249679 N/A N/A 201735 201754 ATTGCACTTATTCCTAGAAC  29  995 1249705 N/A N/A 202858 202877 ACTTTGTAAACAATAAATAA 100  996 1249731 N/A N/A 203355 203374 TCTACCATCTTCCTTTGGCA  35  997 1249757 N/A N/A 203931 203950 CCTAAGAACCTTAATCAGTC  51  998 1249783 N/A N/A 206377 206396 CCTATAACTTATCCTAGGGA  82  999 1249809 N/A N/A 208139 208158 ATTTTCCTCTAATCTATGAA  49 1000 1249835 N/A N/A 209449 209468 GTTCACTTAATATAATATAT  62 1001 1249861 N/A N/A 210870 210889 GTATTTACCCACATTTATTC  70 1002 1249887 N/A N/A 213850 213869 ATTTTTTAAACAATTATCTT  78 1003 1249913 N/A N/A 216831 216850 ATATTATATTCAAATACAAA  86 1004 1249939 N/A N/A 222281 222300 TTTCATAAATTAAATTCTAC  96 1005 1249965 N/A N/A 226213 226232 TGGTTATTATACAATAATTA  76 1006 1249991 N/A N/A 229542 229561 ACTTTTTTTACTATTAGGGA  58 1007 1250017 N/A N/A 231902 231921 TGTGATTTCAACATTAAGAA  34 1008 1250043 N/A N/A 234957 234976 AATATTTTCTCTTAATTGCA  84 1009 1250069 N/A N/A 236196 236215 CAGGTCTTAATAAATTTTGC  25 1010 1250095 N/A N/A 237827 237846 AGTCATATAATCATCTGCGA  32 1011 1250121 N/A N/A 241678 241697 ATTATATTAATATTTTGATC  92 1012 1250147 N/A N/A 243864 243883 GCCTCATATTCAATTATATA  28 1013 1250173 N/A N/A 247187 247206 ACTGTTCTTTCTAATTGGTA  48 1014 1250199 N/A N/A 250509 250528 GATCAAAATTCTATTTGACA  22 1015 1250225 4774 4793 254142 254161 ACCCAGTTTTTTCATTGCAT  25 1016 255535 255554 1250251 N/A N/A 255125 255144 TACATTTTCTCATACAGTAA  59 1017 1250277 N/A N/A 257136 257155 TTCTTTTCATATATTACTCC  37 1018 1250302 N/A N/A 259524 259543 TAAGTAGTGTAAATAGGGAA  55 1019 260901 260920

TABLE 15 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  909602 7311 7330 263839 263858 GGCTAAACAATACTGCAGGA 21 1020  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA 16  227  910391 N/A N/A 259525 259544 GTAAGTAGTGTAAATAGGGA 58  404 260902 260921 1248336  114  133 112527 112546 TAGAAAGTAAAATCTCACAT 60 1021 1248362  403  422 168948 168967 ATTTTCATCATCCTCATCCT 37 1022 1248388 1067 1086 183414 183433 ACAACTGCAATCCTATTAGC 53 1023 1248414 1761 1780 188570 188589 AGCTCTTTTTCACTTTTGGA 19 1024 1248440 2385 2404 199942 199961 CTGGCTATACTCATTGCTCT 22 1025 1248466 2771 2790 215400 215419 GTTCCATTAAACTAAGGCTC 18 1026 1248492† 3756 3775 238221 238240 TCAAGGGATTCCTCAGGTTC 36 1027 1248518 4062 4081 243234 243253 ACTTGAAAACCATATGCAAC 34 1028 1248543 4601 4620 253606 253625 ACAGGTTGTCTTCATACTTG 21 1029 1248569 6261 6280 262789 262808 CTGATATCTTTCCCTTTGTC 56 1030 1248595 7026 7045 263554 263573 AAAACAACTCTTTAATGCTT 48 1031 1248646 7432 7451 263960 263979 GCTTAAATCATCATTTTTGT 34 1032 1248671 7535 7554 264063 264082 AGTGACAGCTTCAAACTATA 45 1033 1248696 7888 7907 264416 264435 CTTTTAATTTCTCATTTTAC 54 1034 1248721 8109 8128 264637 264656 GCCTCTTTCAATGATAAGGC 43 1035 1248747 8387 8406 264915 264934 AGCTTCAGTATAAAGAATCT 64 1036 1248773 8538 8557 265066 265085 TGGCATTTCAAAGATAGAAA 43 1037 1248799 8662 8681 265190 265209 CACTCTTCTTAATTAACTTC 62 1038 1248823 N/A N/A 112776 112795 AGGAAGATTTTAAATTGCAC 61 1039 1248849 N/A N/A 114925 114944 TTTCTTGTATTTACTTGCCT 59 1040 1248875 N/A N/A 118847 118866 AACTTTCTAACACTTAGGCA 59 1041 1248901 N/A N/A 124966 124985 ATGAAGGTATTTAAAATCTA 68 1042 1248927 N/A N/A 128432 128451 GAGAACATTTTTAAATTAAC 66 1043 1248952 N/A N/A 132130 132149 AGATGTAATTCTATTACATA 92 1044 1248978 N/A N/A 142265 142284 TCAATTATATTTAATTGACA 97 1045 1249004 N/A N/A 145404 145423 GATAAAATCTCTAACAATTA 83 1046 1249030 N/A N/A 146412 146431 GCAAATTAAAATAATGGGTT 71 1047 1249056 N/A N/A 150294 150313 TTTTTAACAATTATAAGTAA 72 1048 1249082 N/A N/A 155779 155798 CACCATCATTCACTTAGATT 74 1049 1249108 N/A N/A 157867 157886 CAAGAACTCATTCAACCGTC 74 1050 1249134 N/A N/A 163446 163465 CCATTTATTCCTTATAGCAA 65 1051 1249160 N/A N/A 167788 167807 GGTATTCAAATCATATTTCA 21 1052 1249186 N/A N/A 171261 171280 ATTCAAATATTTTCTAGGCC 44 1053 1249212 N/A N/A 172280 172299 CAGGAAGCAAATACAAGCCC 25 1054 1249238 N/A N/A 173006 173025 ATCACAAGCATAATTTCTCA 36 1055 1249264 N/A N/A 174698 174717 TTTTTGCTAATCTTACAGCA 49 1056 1249290 N/A N/A 175997 176016 GGCAGATAAACCTTTTATAA 51 1057 1249316 N/A N/A 176969 176988 TGACACTTAAAAACTTACTC 21 1058 1249342 N/A N/A 178010 178029 CTAATAGTCCATCTAGATTA 44 1059 1249368 N/A N/A 178516 178535 GTGGCATTTTTCTTTTTGAA 34 1060 1249394 N/A N/A 179942 179961 ATGACTTTCATATTTAATAA 67 1061 1249420 N/A N/A 180753 180772 GAAGTTTAAAACTTTAGTGC 29 1062 1249446 N/A N/A 181986 182005 TTTATTACTTTACAGTGCTA 23 1063 1249472 N/A N/A 183795 183814 ATAAGACAACACATTTTCAA 52 1064 1249498 N/A N/A 184734 184753 AATATAAGCTCAAATTGCAT 62 1065 1249524 N/A N/A 185624 185643 ATCCACTTCATCATCACAAA 39 1066 1249550 N/A N/A 186441 186460 ATTTATATAATAACAGAATC 75 1067 1249576 N/A N/A 189618 189637 GCTTAATGCATTAATATTGC 13 1068 1249602 N/A N/A 191017 191036 GTTTGACATTTTCAGTATTA 14 1069 1249628 N/A N/A 194924 194943 ACTTCATCATTTAAGTATTA 53 1070 1249654 N/A N/A 200423 200442 CTACAAAATTTTAAACACTT 84 1071 1249680 N/A N/A 201767 201786 AACGAAAACACTCTCAGTCT 52 1072 1249706 N/A N/A 202859 202878 AACTTTGTAAACAATAAATA 91 1073 1249732 N/A N/A 203360 203379 AACTGTCTACCATCTTCCTT 45 1074 1249758 N/A N/A 204009 204028 TTGCATACACTTAAAGCTCA 69 1075 1249784 N/A N/A 206383 206402 ACCTAACCTATAACTTATCC 79 1076 1249810 N/A N/A 208150 208169 ATCTTAACAATATTTTCCTC 43 1077 1249836 N/A N/A 209454 209473 GCTTTGTTCACTTAATATAA 27 1078 1249862 N/A N/A 210961 210980 ATTTACAATTTATTTATGCA 68 1079 1249888 N/A N/A 213855 213874 ACGAAATTTTTTAAACAATT 82 1080 1249914 N/A N/A 216848 216867 GGCTATATTTTAAACATATA 54 1081 1249940 N/A N/A 222282 222301 TTTTCATAAATTAAATTCTA 86 1082 1249966 N/A N/A 226251 226270 GCTACTATAATTATACAATA 43 1083 1249992 N/A N/A 229546 229565 ATTGACTTTTTTTACTATTA 42 1084 1250018 N/A N/A 231976 231995 ACAAAATAATTAACATTTCT 89 1085 1250044 N/A N/A 235015 235034 CACTAACTACTAACACTTCC 69 1086 1250070 N/A N/A 236284 236303 TGAGGATCCATATTCAGGGT 17 1087 1250096 N/A N/A 238319 238338 AGACATTTAAATAAATAGGA 84 1088 1250122 N/A N/A 241687 241706 ATCATTTTCATTATATTAAT 76 1089 1250148 N/A N/A 243917 243936 CTGCATGTAACCTTTATACA 20 1090 1250174 N/A N/A 247339 247358 TTTCAAAAAATCATACAAAC 96 1091 1250200 N/A N/A 250553 250572 CTTTTTTCCCAAAATTATAA 65 1092 1250226 4775 4794 254143 254162 AACCCAGTTTTTTCATTGCA 23 1093 255536 255555 1250252 N/A N/A 255193 255212 CTACTACTCACTAATTCAAA 71 1094 1250278 N/A N/A 257137 257156 GTTCTTTTCATATATTACTC 24 1095

TABLE 16 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  17  227 1248337  132  151 112545 112564 TCAGAATTTTTACTGGAGTA  73 1096 1248363  413  432 168958 168977 GCTTTGGGCCATTTTCATCA  19 1097 1248389 1069 1088 183416 183435 GAACAACTGCAATCCTATTA  33 1098 1248415 1767 1786 188576 188595 TTTTTCAGCTCTTTTTCACT  49 1099 1248441 2386 2405 199943 199962 ACTGGCTATACTCATTGCTC  18 1100 1248467 2773 2792 215402 215421 AAGTTCCATTAAACTAAGGC  28 1101 1248493† 3814 3833 240232 240251 GCTTATCTGACAACACTTGA  10 1102 1248519 4064 4083 243236 243255 ACACTTGAAAACCATATGCA  23 1103 1248544 4790 4809 254158 254177 TTTGTGGTTTCTTTGAACCC  36 1104 1248570 6275 6294 262803 262822 ACTTTTTACTTTCCCTGATA  38 1105 1248596 7036 7055 263564 263583 ATGTAAAAATAAAACAACTC  78 1106 1248621 7314 7333 263842 263861 GATGGCTAAACAATACTGCA  35 1107 1248647 7434 7453 263962 263981 GTGCTTAAATCATCATTTTT  38 1108 1248672 7554 7573 264082 264101 GGCAAGATAAACATGCAGCA  24 1109 1248697 7890 7909 264418 264437 TACTTTTAATTTCTCATTTT  63 1110 1248722 8118 8137 264646 264665 TTTCTTTAAGCCTCTTTCAA  64 1111 1248748 8402 8421 264930 264949 ACACTACAAGTCAATAGCTT  64 1112 1248774 8540 8559 265068 265087 AATGGCATTTCAAAGATAGA  55 1113 1248800 8663 8682 265191 265210 ACACTCTTCTTAATTAACTT  75 1114 1248824 N/A N/A 112777 112796 TAGGAAGATTTTAAATTGCA  80 1115 1248850 N/A N/A 115244 115263 TTGTTCCCCATTAATGTTTA  76 1116 1248876 N/A N/A 118851 118870 TTTTAACTTTCTAACACTTA 108 1117 1248902 N/A N/A 125043 125062 ATTACTTTCACATCTAAGCT  96 1118 1248928 N/A N/A 128487 128506 TAGAGCCATATTTTAATAAT  63 1119 128530 128549 128573 128592 1248953 N/A N/A 133376 133395 CTATTCTTTTCAAAATATTA  89 1120 1248979 N/A N/A 142299 142318 GTTAATAATCCAATATTTTA  83 1121 1249005 N/A N/A 145407 145426 ATTGATAAAATCTCTAACAA  86 1122 1249031 N/A N/A 146427 146446 GGCACTATAACCAATGCAAA  48 1123 1249057 N/A N/A 150300 150319 ATTTACTTTTTAACAATTAT  58 1124 1249083 N/A N/A 155814 155833 ACCTCCTCTACCATTAGCAC  66 1125 1249109 N/A N/A 158023 158042 ACATCTAACTTTCCTAGGAA  57 1126 1249135 N/A N/A 163447 163466 ACCATTTATTCCTTATAGCA  62 1127 1249161 N/A N/A 169321 169340 TTGTCCTTCCTTAATTCCCG  17 1128 1249187 N/A N/A 171276 171295 TCCATACCTTATCTAATTCA  22 1129 1249213 N/A N/A 172339 172358 ACCTGCATCTCCTCAGGCCT  46 1130 1249239 N/A N/A 173081 173100 TTTATTTAAATATCAAATAA  74 1131 1249265 N/A N/A 174709 174728 TGAGAGTTTCCTTTTTGCTA  31 1132 1249291 N/A N/A 176071 176090 GTACATTTTTCAAAAGAACA  20 1133 1249317 N/A N/A 176973 176992 TTTATGACACTTAAAAACTT  69 1134 1249343 N/A N/A 178011 178030 TCTAATAGTCCATCTAGATT  55 1135 1249369 N/A N/A 178752 178771 ATCTATCATATATTCAGCCT  32 1136 1249395 N/A N/A 179943 179962 AATGACTTTCATATTTAATA  52 1137 1249421 N/A N/A 180757 180776 CCATGAAGTTTAAAACTTTA  57 1138 1249447 N/A N/A 182021 182040 TTGTCATCAATCATAATCTC  25 1139 1249473 N/A N/A 183813 183832 ATTACTTTCAACATGAGTAT  32 1140 1249499 N/A N/A 184743 184762 TTCATTGCAAATATAAGCTC  36 1141 1249525 N/A N/A 185632 185651 ATTTATTAATCCACTTCATC  61 1142 1249551 N/A N/A 186487 186506 ATTTCTCTCACCTTACCCAG  40 1143 1249577 N/A N/A 189660 189679 GATATTAACTAAATTAGAAC  64 1144 1249603 N/A N/A 191114 191133 ACAATAATTCCTAATATTTT 111 1145 1249629 N/A N/A 195681 195700 CCTGATGCAAATCTTACCAT  44 1146 1249655 N/A N/A 200429 200448 GTAGGACTACAAAATTTTAA  29 1147 1249681 N/A N/A 201780 201799 CTGCAGATAATAAAACGAAA  78 1148 1249707 N/A N/A 202870 202889 CCTTAATACATAACTTTGTA  48 1149 1249733 N/A N/A 203483 203502 CAAGAAGAATTTCAACCAAA  80 1150 1249759 N/A N/A 204088 204107 TTCCAAGATTCTATTGGCAA  20 1151 1249785 N/A N/A 206386 206405 ATGACCTAACCTATAACTTA  67 1152 1249811 N/A N/A 208227 208246 CACTTTCTGCAAAATAGGTA  15 1153 1249837 N/A N/A 209581 209600 TTGTTGCTCCCATTTACCCT  39 1154 1249863 N/A N/A 212405 212424 GTTTTTTTTTCCTTTAGTTC  14 1155 1249889 N/A N/A 214622 214641 ACTTTGTTTCCCTTTATCTA  52 1156 1249915 N/A N/A 216892 216911 AGATTGTTTTAATCTAGCTA  63 1157 1249941 N/A N/A 222289 222308 GTCAGCCTTTTCATAAATTA  41 1158 1249967 N/A N/A 226278 226297 GTCCCAATTTTTATTAAGAC  24 1159 1249993 N/A N/A 229592 229611 CTTAGTTTATATGACAGCCT  27 1160 1250019 N/A N/A 231980 231999 AGTGACAAAATAATTAACAT  79 1161 1250045 N/A N/A 235019 235038 CAACCACTAACTACTAACAC  62 1162 1250071 N/A N/A 236527 236546 TTCTCATTTTAATATATCTA  57 1163 1250097 N/A N/A 238394 238413 GTATAGATGATTACTAGATA  67 1164 1250123 N/A N/A 241689 241708 ATATCATTTTCATTATATTA  82 1165 1250149 N/A N/A 244053 244072 ATGCATAATCCCATTATACA  19 1166 1250175 N/A N/A 247346 247365 ACATCACTTTCAAAAAATCA  66 1167 1250201 N/A N/A 250554 250573 TCTTTTTTCCCAAAATTATA  82 1168 1250227 4776 4795 254144 254163 GAACCCAGTTTTTTCATTGC  18 1169 255537 255556 1250253 N/A N/A 255196 255215 TGTCTACTACTCACTAATTC  50 1170 1250279 N/A N/A 257139 257158 ATGTTCTTTTCATATATTAC  38 1171 1250303 N/A N/A 259564 259583 TTGGAGAGCTGAGGTAACTT  38 1172 260941 260960

TABLE 17 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  23  227 1248338  133  152 112546 112565 TTCAGAATTTTTACTGGAGT  59 1173 1248364  440  459 168985 169004 ATTTTCCTGCTTCCAAGTCA  48 1174 1248390 1102 1121 183449 183468 CCATTGCAAACATTTATTTC  37 1175 1248416 1774 1793 188583 188602 TCTTCTGTTTTTCAGCTCTT  40 1176 1248442 2388 2407 199945 199964 ATACTGGCTATACTCATTGC  55 1177 1248468 2777 2796 215406 215425 AACCAAGTTCCATTAAACTA  53 1178 1248494† 3820 3839 240238 240257 TTCTATGCTTATCTGACAAC  49 1179 1248520 4212 4231 246309 246328 GACAAAGCTCTCAGTGGCCT  63 1180 1248545 4846 4865 259762 259781 GGTTACAAAATCAAAGACCA  33 1181 1248571 6276 6295 262804 262823 TACTTTTTACTTTCCCTGAT  58 1182 1248597 7039 7058 263567 263586 GTTATGTAAAAATAAAACAA 103 1183 1248622 7315 7334 263843 263862 AGATGGCTAAACAATACTGC  62 1184 1248648 7435 7454 263963 263982 TGTGCTTAAATCATCATTTT  55 1185 1248673 7596 7615 264124 264143 TTAGACTTCTGAACAGTGGA  47 1186 1248698 7891 7910 264419 264438 ATACTTTTAATTTCTCATTT  82 1187 1248723 8196 8215 264724 264743 GACTGATGATTACTGAATAA  57 1188 1248749 8408 8427 264936 264955 ACCAACACACTACAAGTCAA  52 1189 1248775 8543 8562 265071 265090 TTAAATGGCATTTCAAAGAT  70 1190 1248801 8664 8683 265192 265211 TACACTCTTCTTAATTAACT  88 1191 1248825 N/A N/A 112974 112993 ATCTGCTTCATTATATCTCT  64 1192 1248851 N/A N/A 115394 115413 TTTTGATATTCAATTTACCT  72 1193 1248877 N/A N/A 118854 118873 ACATTTTAACTTTCTAACAC  82 1194 1248903 N/A N/A 125052 125071 AGCATATTAATTACTTTCAC  64 1195 1248929 N/A N/A 128488 128507 ATAGAGCCATATTTTAATAA  85 1196 128531 128550 128574 128593 1248954 N/A N/A 134288 134307 CTTTAGAGATAATCTAGTCC  77 1197 1248980 N/A N/A 142450 142469 GCTTAAGAACACATTAGTGA  78 1198 1249006 N/A N/A 145828 145847 ATGTTGTATTCTAATTATCA  83 1199 1249032 N/A N/A 146480 146499 AATTAAATCCCTACTTTATA  92 1200 1249058 N/A N/A 150301 150320 AATTTACTTTTTAACAATTA 100 1201 1249084 N/A N/A 155818 155837 TCTCACCTCCTCTACCATTA  64 1202 1249110 N/A N/A 158105 158124 TGCTTTTCTTTAACAGAAAT  86 1203 1249136 N/A N/A 163471 163490 AAGCACTATTTTAAGAGCTA  85 1204 1249162 N/A N/A 169323 169342 TTTTGTCCTTCCTTAATTCC  51 1205 1249188 N/A N/A 171502 171521 GAAACATAAACATCAAATAA  86 1206 1249214 N/A N/A 172351 172370 CTTCACATTTCAACCTGCAT  40 1207 1249240 N/A N/A 173085 173104 ATGTTTTATTTAAATATCAA  64 1208 1249266 N/A N/A 175089 175108 GGACACTATTTAATGAATCA  20 1209 1249292 N/A N/A 176648 176667 TTAATTTATTTCATCAGTCA  77 1210 1249318 N/A N/A 177473 177492 ATTTTGCAATTCATTTGTTA  40 1211 1249344 N/A N/A 178020 178039 AGCATCAAATCTAATAGTCC  22 1212 1249370 N/A N/A 178775 178794 GCTTATCTTTCCTTTTCTTA  28 1213 1249396 N/A N/A 179945 179964 GTAATGACTTTCATATTTAA  37 1214 1249422 N/A N/A 180767 180786 GCCTTCACCACCATGAAGTT  36 1215 1249448 N/A N/A 182025 182044 GGCATTGTCATCAATCATAA  19 1216 1249474 N/A N/A 183842 183861 AAACATTTTTTAATATGGCA  43 1217 1249500 N/A N/A 184763 184782 ATAACATTCTTATATCAGCA  31 1218 1249526 N/A N/A 185637 185656 TATACATTTATTAATCCACT  46 1219 1249552 N/A N/A 186521 186540 ATGTCTGTTTTATACAGGCA  58 1220 1249578 N/A N/A 189685 189704 CTTCTCTTCACATATAAAAA  54 1221 1249604 N/A N/A 191169 191188 TAGTTTTTCAATACAAACAC  48 1222 1249630 N/A N/A 199983 200002 GCAGGACTTTTAACATACCT  65 1223 1249656 N/A N/A 200498 200517 ATTCAGATAAAATCTGCAAC  77 1224 1249682 N/A N/A 201811 201830 TTATTTCTCACAAATACACA  72 1225 1249708 N/A N/A 202877 202896 CCATTTCCCTTAATACATAA  30 1226 1249734 N/A N/A 203538 203557 TGACATAAAATTTTATATTA  93 1227 1249760 N/A N/A 204253 204272 TTGGTTTAAATTAAAAGGAA  54 1228 1249786 N/A N/A 206387 206406 TATGACCTAACCTATAACTT  64 1229 1249812 N/A N/A 208303 208322 CTTTATTTTTTTTCTAGTTA  65 1230 1249838 N/A N/A 209815 209834 AAGGTGATATATACAAGAAC  45 1231 1249864 N/A N/A 212579 212598 GTTAAATTTATTACTATATT  99 1232 1249890 N/A N/A 214990 215009 GTCTCTGATCTTTCTAGCCC  29 1233 1249916 N/A N/A 216948 216967 ATCAACACTTAAATTACATA  53 1234 1249942 N/A N/A 222521 222540 ATTCTCTTTTCAACTTCAAT  57 1235 1249968 N/A N/A 226381 226400 CCAATATATTTAAATATGAT  88 1236 1249994 N/A N/A 229604 229623 GTATAATTCATTCTTAGTTT  40 1237 1250020 N/A N/A 231981 232000 AAGTGACAAAATAATTAACA  76 1238 1250046 N/A N/A 235022 235041 ATCCAACCACTAACTACTAA  62 1239 1250072 N/A N/A 236528 236547 CTTCTCATTTTAATATATCT  43 1240 1250098 N/A N/A 238454 238473 GCATTTTTTTTCAAACAGCA  28 1241 1250124 N/A N/A 241720 241739 ACATTTGTATCACCAATTAA  70 1242 1250150 N/A N/A 244154 244173 CTTTTATCCTAACATAGATA  91 1243 1250176 N/A N/A 247429 247448 GCAAATTTACCTCAAAGGAT  47 1244 1250202 N/A N/A 250658 250677 AAACAATTTCCCTCTAACTA  80 1245 1250228 4778 4797 254146 254165 TTGAACCCAGTTTTTTCATT  49 1246 255539 255558 1250254 N/A N/A 255310 255329 TCTTTTCACATTACTAGGCT  34 1247 1250280 N/A N/A 257269 257288 AGATAATTCCAAACTTCTCA  43 1248 1250304 N/A N/A 259587 259606 AAAATTCCTTGCAAAACCAG  62 1249 260964 260983

TABLE 18 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  20  227 1248339  139  158 112552 112571 CAATTCTTCAGAATTTTTAC  75 1250 1248365  446  465 168991 169010 GAAGAGATTTTCCTGCTTCC  25 1251 1248391 1103 1122 183450 183469 GCCATTGCAAACATTTATTT  26 1252 1248417 1818 1837 188627 188646 TTTTTCTCTTCTTCTCCAGA  43 1253 1248443 2398 2417 199955 199974 GTTGGTCAAAATACTGGCTA  23 1254 1248469 2798 2817 215427 215446 ACAATCCTTCCACATTTGCC  31 1255 1248495† 3821 3840 240239 240258 CTTCTATGCTTATCTGACAA  15 1256 1248521 4213 4232 246310 246329 GGACAAAGCTCTCAGTGGCC  28 1257 1248546 4847 4866 259763 259782 TGGTTACAAAATCAAAGACC  33 1258 1248572 6280 6299 262808 262827 TTTTTACTTTTTACTTTCCC  44 1259 1248598 7040 7059 263568 263587 GGTTATGTAAAAATAAAACA  86 1260 1248623 7317 7336 263845 263864 GAAGATGGCTAAACAATACT  57 1261 1248649 7437 7456 263965 263984 AGTGTGCTTAAATCATCATT  39 1262 1248674 7611 7630 264139 264158 ATATGGCTTCCCATATTAGA  32 1263 1248699 7894 7913 264422 264441 AAGATACTTTTAATTTCTCA  53 1264 1248724 8217 8236 264745 264764 GTGTAAACAAACATTGGAAA  59 1265 1248750 8409 8428 264937 264956 CACCAACACACTACAAGTCA  40 1266 1248776 8552 8571 265080 265099 AATCTACCTTTAAATGGCAT  56 1267 1248802 8665 8684 265193 265212 ATACACTCTTCTTAATTAAC  70 1268 1248826 N/A N/A 113346 113365 GCACCTTCTATAATATCAAC  78 1269 1248852 N/A N/A 115559 115578 TCTCATGTCCAATTTAGTCC  50 1270 1248878 N/A N/A 118858 118877 TTTCACATTTTAACTTTCTA  67 1271 1248904 N/A N/A 125245 125264 AAGATGCTTATTAATATCTT  84 1272 1248930 N/A N/A 128489 128508 CATAGAGCCATATTTTAATA  80 1273 128532 128551 128575 128594 1248955 N/A N/A 134475 134494 ACCTAGTATATAACTTCCCT  85 1274 1248981 N/A N/A 142643 142662 CTAATAATCCATAAATGTAA  62 1275 1249007 N/A N/A 145921 145940 TGAAGATAATTAAATGCTAA  83 1276 1249033 N/A N/A 146488 146507 AGATTTAGAATTAAATCCCT  85 1277 1249059 N/A N/A 150308 150327 GTTTCTCAATTTACTTTTTA  51 1278 1249085 N/A N/A 155820 155839 TTTCTCACCTCCTCTACCAT  82 1279 1249111 N/A N/A 158120 158139 TCCTAAGACACATTTTGCTT  67 1280 1249137 N/A N/A 163508 163527 TTTTAATAAAAATCTACACA  83 1281 1249163 N/A N/A 169407 169426 TTTTGCTTCTCAACATTATT  21 1282 1249189 N/A N/A 171503 171522 TGAAACATAAACATCAAATA  73 1283 1249215 N/A N/A 172357 172376 GGCTGGCTTCACATTTCAAC  33 1284 1249241 N/A N/A 173089 173108 AATCATGTTTTATTTAAATA 116 1285 1249267 N/A N/A 175113 175132 CCATGATATTTTATATCTCA  22 1286 1249293 N/A N/A 176665 176684 AAGTTTCTAAATCATTGTTA  55 1287 1249319 N/A N/A 177486 177505 ACTAATGAAATTAATTTTGC  54 1288 1249345 N/A N/A 178124 178143 ATCTAATTAACCATCAAATA  63 1289 1249371 N/A N/A 178812 178831 CCTTTTCCATATCATGGCCA  16 1290 1249397 N/A N/A 179978 179997 ACTATTTAAGAAAATATTCA  74 1291 1249423 N/A N/A 180772 180791 ACCATGCCTTCACCACCATG  28 1292 1249449 N/A N/A 182095 182114 CTTGGTCTTTCATCAAGACC  54 1293 1249475 N/A N/A 183843 183862 TAAACATTTTTTAATATGGC  43 1294 1249501 N/A N/A 184814 184833 TGGTTAGCAAATCTATGTTA  22 1295 1249527 N/A N/A 185638 185657 CTATACATTTATTAATCCAC  19 1296 1249553 N/A N/A 186540 186559 CCTGTTTTAATATATGCCAA  33 1297 1249579 N/A N/A 189791 189810 AGTAATGAAAATAATACTAT  73 1298 1249605 N/A N/A 191172 191191 GTATAGTTTTTCAATACAAA  25 1299 1249631 N/A N/A 200015 200034 TCATCATTACCAAAGCACCA  30 1300 1249657 N/A N/A 200521 200540 GACTGCTACACATTATGTTA  25 1301 1249683 N/A N/A 201812 201831 ATTATTTCTCACAAATACAC  49 1302 1249709 N/A N/A 202878 202897 TCCATTTCCCTTAATACATA  28 1303 1249735 N/A N/A 203543 203562 AAACATGACATAAAATTTTA  76 1304 1249761 N/A N/A 204276 204295 TGCTTACTTTCTATTAAGCA  76 1305 1249787 N/A N/A 206390 206409 TTTTATGACCTAACCTATAA  79 1306 1249813 N/A N/A 208338 208357 GTAAGTTTTAAAATTTGGAA  75 1307 1249839 N/A N/A 209913 209932 TGCATATCATCTAATTTTTA  34 1308 1249865 N/A N/A 212582 212601 TTTGTTAAATTTATTACTAT  76 1309 1249891 N/A N/A 215059 215078 GTCAATAAAATTAATATTAT  75 1310 1249917 N/A N/A 216950 216969 ATATCAACACTTAAATTACA 110 1311 1249943 N/A N/A 222556 222575 CTGATGTCAACCATAAGTAC  32 1312 1249969 N/A N/A 226405 226424 TTATTCCTAAAATCAACAAT  69 1313 1249995 N/A N/A 229683 229702 GTCAAGTTAAACATTCCTCA  21 1314 1250021 N/A N/A 232043 232062 CTACACTTTTATATTAGTGC   8 1315 1250047 N/A N/A 235023 235042 TATCCAACCACTAACTACTA  57 1316 1250073 N/A N/A 236627 236646 CATGTTTTTCTAATTTCCTA  40 1317 1250099 N/A N/A 238495 238514 ATATCTAATTACATAAATTA  74 1318 1250125 N/A N/A 241760 241779 TAGTTATTAATTAAATTGAA 101 1319 1250151 N/A N/A 244191 244210 AAGAGTTTCCTTATATTCAA  34 1320 1250177 N/A N/A 247430 247449 AGCAAATTTACCTCAAAGGA  35 1321 1250203 N/A N/A 250861 250880 GCCTTGCTAAATACTAGAAA  38 1322 1250229 4779 4798 254147 254166 TTTGAACCCAGTTTTTTCAT  42 1323 255540 255559 1250255 N/A N/A 255330 255349 GTTAAACTCTCTAAAATCTT  76 1324 1250281 N/A N/A 257335 257354 TCTCTAACTTCATCTTGGCC  52 1325 1250305 N/A N/A 259588 259607 AAAAATTCCTTGCAAAACCA  55 1326 260965 260984

TABLE 19 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  23  227 1248340  140  159 112553 112572 GCAATTCTTCAGAATTTTTA  51 1327 1248366  555  574 170026 170045 GCTTTCCCTTTATTCAATAC   6 1328 1248392 1136 1155 183483 183502 TGATATTTATTTCAAAGGAA  27 1329 1248418 1820 1839 188629 188648 CATTTTTCTCTTCTTCTCCA  47 1330 1248444 2399 2418 199956 199975 TGTTGGTCAAAATACTGGCT  21 1331 1248470 2799 2818 215428 215447 GACAATCCTTCCACATTTGC  34 1332 1248496† 3828 3847 240246 240265 TTGCCTTCTTCTATGCTTAT  10 1333 1248522 4319 4338 247753 247772 TGATACTGAATATTAGCCAA  19 1334 1248547 4942 4961 259858 259877 GTTTGTCATTTCTTGACTCT  30 1335 1248573 6284 6303 262812 262831 TTTCTTTTTACTTTTTACTT  60 1336 1248599 7055 7074 263583 263602 CATGTACATTTAATGGGTTA  62 1337 1248624 7337 7356 263865 263884 TGTCAACCTTACCAAGAGCA  25 1338 1248650 7439 7458 263967 263986 GTAGTGTGCTTAAATCATCA  27 1339 1248675 7613 7632 264141 264160 ATATATGGCTTCCCATATTA  46 1340 1248700 7895 7914 264423 264442 GAAGATACTTTTAATTTCTC  43 1341 1248725 8219 8238 264747 264766 CTGTGTAAACAAACATTGGA  30 1342 1248751 8410 8429 264938 264957 TCACCAACACACTACAAGTC  52 1343 1248777 8553 8572 265081 265100 AAATCTACCTTTAAATGGCA  66 1344 1248803 8666 8685 265194 265213 AATACACTCTTCTTAATTAA  71 1345 1248827 N/A N/A 113347 113366 AGCACCTTCTATAATATCAA  64 1346 1248853 N/A N/A 115616 115635 TATCTCTCCTACCTTTCCCT  73 1347 1248879 N/A N/A 119056 119075 GCATAATTTACTAACAGTTT  65 1348 1248905 N/A N/A 125264 125283 ATACTTTTTCCAAAGTATTA 112 1349 1248931 N/A N/A 128490 128509 CCATAGAGCCATATTTTAAT  65 1350 128533 128552 128576 128595 1248956 N/A N/A 134574 134593 AGGTGATTCACCTTATTTTA  73 1351 1248982 N/A N/A 142705 142724 TTCTTTTTCCATTTGAATAA  87 1352 1249008 N/A N/A 145922 145941 CTGAAGATAATTAAATGCTA  59 1353 1249034 N/A N/A 146537 146556 GAAAATATTTTTCAACATTA  76 1354 1249060 N/A N/A 150312 150331 TATTGTTTCTCAATTTACTT  71 1355 1249086 N/A N/A 155823 155842 TCATTTCTCACCTCCTCTAC  76 1356 1249112 N/A N/A 158146 158165 AGATATTCCATTAAATGATT  70 1357 1249138 N/A N/A 163512 163531 CTTTTTTTAATAAAAATCTA  80 1358 1249164 N/A N/A 169771 169790 GCCATAGGAATTCTTAGCAA   5 1359 1249190 N/A N/A 171560 171579 AGGTAAGAAAACATTATTGC  25 1360 1249216 N/A N/A 172381 172400 TGGCATACCTTAATAGATTT  17 1361 1249242 N/A N/A 173200 173219 GTGCATATATTAACTTAAAA  22 1362 1249268 N/A N/A 175218 175237 CAGTAGATAACTAAATGATA  26 1363 1249294 N/A N/A 176724 176743 CAAGTTTTTACGCTTGTGGT  12 1364 1249320 N/A N/A 177528 177547 ATTATTCACCATTATAGCCT  23 1365 1249346 N/A N/A 178128 178147 TCATATCTAATTAACCATCA  24 1366 1249372 N/A N/A 178821 178840 CCTTATCTCCCTTTTCCATA  59 1367 1249398 N/A N/A 179983 180002 AAACAACTATTTAAGAAAAT  97 1368 1249424 N/A N/A 180774 180793 CTACCATGCCTTCACCACCA  23 1369 1249450 N/A N/A 182096 182115 CCTTGGTCTTTCATCAAGAC  40 1370 1249476 N/A N/A 183849 183868 ACCAAATAAACATTTTTTAA  90 1371 1249502 N/A N/A 184829 184848 TTTTGATTATACAAATGGTT  28 1372 1249528 N/A N/A 185639 185658 GCTATACATTTATTAATCCA  17 1373 1249554 N/A N/A 186541 186560 TCCTGTTTTAATATATGCCA  21 1374 1249580 N/A N/A 189806 189825 TAGCTTTTTCATTATAGTAA  21 1375 1249606 N/A N/A 191229 191248 TCATATTTCCACTTACTCTA  34 1376 1249632 N/A N/A 200022 200041 TGTTTTTTCATCATTACCAA  18 1377 1249658 N/A N/A 200522 200541 AGACTGCTACACATTATGTT  61 1378 1249684 N/A N/A 201831 201850 ACAGAATAAAAACTTGGCCA  37 1379 1249710 N/A N/A 202879 202898 TTCCATTTCCCTTAATACAT  17 1380 1249736 N/A N/A 203557 203576 ATAACTCTCATATCAAACAT  60 1381 1249762 N/A N/A 204279 204298 AACTGCTTACTTTCTATTAA  79 1382 1249788 N/A N/A 206493 206512 GTGATTTTCCACATTGACTT  16 1383 1249814 N/A N/A 208371 208390 GTACCAAACTATCTTGCTTA  28 1384 1249840 N/A N/A 209949 209968 AATCTATTAACTATGAGTCA  55 1385 1249866 N/A N/A 212710 212729 ATTAATTTCTTAATAATATT  93 1386 1249892 N/A N/A 215178 215197 CTGATTTTAAAAAATTGGTT  42 1387 1249918 N/A N/A 216958 216977 TGAGAATAATATCAACACTT  22 1388 1249944 N/A N/A 222572 222591 ACAATCTAAATTAATACTGA  73 1389 1249970 N/A N/A 226410 226429 ATAATTTATTCCTAAAATCA  77 1390 1249996 N/A N/A 230204 230223 TTGTTTTAATTCTCTAGTTT  45 1391 1250022 N/A N/A 232903 232922 ATAACATTTTTAAAACCACA  60 1392 1250048 N/A N/A 235029 235048 CTCTTTTATCCAACCACTAA  53 1393 1250074 N/A N/A 236628 236647 ACATGTTTTTCTAATTTCCT  30 1394 1250100 N/A N/A 238696 238715 GTACACTTATCAATTATTAC  20 1395 1250126 N/A N/A 241798 241817 CAGTAATTCTCCTAATGAAA  37 1396 1250152 N/A N/A 244728 244747 CTGTATTAAATAATAAGTCC  39 1397 1250178 N/A N/A 247452 247471 CAAGAGGTAATAACACACAT  34 1398 1250204 N/A N/A 251582 251601 TTGTTTTCCCATTTAACGCA  18 1399 1250230 4780 4799 254148 254167 CTTTGAACCCAGTTTTTTCA  38 1400 255541 255560 1250256 N/A N/A 255511 255530 CCTCTTTTCCTGTGTTTCAT  26 1401 255620 255639 1250282 N/A N/A 257421 257440 CTGTTCTCCCATTTAAATCC  36 1402 1250306 N/A N/A 260014 260033 AAAGCACCTCTTCTTACCTA  69 1403

TABLE 20  Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  12  227 1248342  146  165 112559 112578 TCCAATGCAATTCTTCAGAA  73 1404 1248368  561  580 170032 170051 GAGATTGCTTTCCCTTTATT  13 1405 1248394 1175 1194 183522 183541 TAGTACCATTCCCATCCAAT  14 1406 1248420 1823 1842 188632 188651 TGTCATTTTTCTCTTCTTCT  22 1407 1248446 2460 2479 204362 204381 TTAGCAAATTTATACCAGCA  17 1408 1248472 2803 2822 215432 215451 AACTGACAATCCTTCCACAT  56 1409 1248498† 3831 3850 240249 240268 CCTTTGCCTTCTTCTATGCT  11 1410 1248524 4333 4352 247767 247786 GAGATTCACTCCCATGATAC  17 1411 1248549 5004 5023 259920 259939 AGTTTCAGCACACATTCTCC  30 1412 1248575 6290 6309 262818 262837 TCTTGGTTTCTTTTTACTTT  31 1413 1248601 7057 7076 263585 263604 TACATGTACATTTAATGGGT  60 1414 1248626 7342 7361 263870 263889 TACTATGTCAACCTTACCAA  77 1415 1248652 7476 7495 264004 264023 AAACTATACTTACTGTGGTA  63 1416 1248677 7630 7649 264158 264177 GCTTCACTTTACCACTGATA  27 1417 1248702 7897 7916 264425 264444 CTGAAGATACTTTTAATTTC  52 1418 1248727 8271 8290 264799 264818 CCCATATTATATCTGATACA  35 1419 1248753 8413 8432 264941 264960 ATTTCACCAACACACTACAA  57 1420 1248779 8560 8579 265088 265107 ATGATAGAAATCTACCTTTA  65 1421 1248805 8668 8687 265196 265215 CCAATACACTCTTCTTAATT  58 1422 1248829 N/A N/A 113406 113425 GAGTCATTCCACTCTTTAAC  63 1423 1248855 N/A N/A 115837 115856 TGCTCATTATCATCAACCAC  51 1424 1248881 N/A N/A 119211 119230 GCTAAATTCCTATCTTCTAA  59 1425 1248907 N/A N/A 125398 125417 CATCTTAAATTTAAATGATA  72 1426 1248933 N/A N/A 128492 128511 AACCATAGAGCCATATTTTA  98 1427 128535 128554 128578 128597 1248958 N/A N/A 137451 137470 GATGGCTTTTTATTACCTTA  55 1428 1248984 N/A N/A 142797 142816 ACACTTGATTTTAATAAACA  73 1429 1249010 N/A N/A 145983 146002 CATAATTCCTATAATTCTCA  54 1430 1249036 N/A N/A 146652 146671 GTTCAAATCATAATCACAAA  67 1431 1249062 N/A N/A 150352 150371 TCAAGAATTACCATTTGCTC  59 1432 1249088 N/A N/A 155881 155900 TATGTCATAACCTCTAGTGA  80 1433 1249114 N/A N/A 158189 158208 GTTCCATCTTCATCTTGTTC  72 1434 1249140 N/A N/A 163620 163639 ACAAATGATTCTAATTCAAA  69 1435 1249166 N/A N/A 169921 169940 TTATTTATAAATATTGCCCT  32 1436 1249192 N/A N/A 171638 171657 TTATTTATTTCTAATGCTAA 148 1437 1249218 N/A N/A 172471 172490 AGAGACTTTTTAAAATCTAA  27 1438 1249244 N/A N/A 173289 173308 CTTACAAGAATATCTACCAC  66 1439 1249270 N/A N/A 175252 175271 TGTTTAATTTTAATATGAAC  51 1440 1249296 N/A N/A 176727 176746 GGTCAAGTTTTTACGCTTGT  13 1441 1249322 N/A N/A 177540 177559 AATCATGTCTATATTATTCA  26 1442 1249348 N/A N/A 178230 178249 TGCTAATTACTTACTCCTTT  25 1443 1249374 N/A N/A 179082 179101 AAACTTTTCCACATTGAGAC  43 1444 1249400 N/A N/A 180016 180035 TTGACATTAAAAAACAGCAA  39 1445 1249426 N/A N/A 180776 180795 CACTACCATGCCTTCACCAC  33 1446 1249452 N/A N/A 182322 182341 GGGTTCACACACAAACACAA  17 1447 1249478 N/A N/A 183890 183909 GACTTATTTATTAAAATGAC  55 1448 1249504 N/A N/A 184855 184874 ATTGAACAAATATCAATATA  62 1449 1249530 N/A N/A 185655 185674 TTGAGCGATCTAAATAGCTA  27 1450 1249556 N/A N/A 187159 187178 CTGACCTCAACATTTAGGTT  35 1451 1249582 N/A N/A 189873 189892 AAGATCATAATAACTTTTTC  75 1452 1249608 N/A N/A 191236 191255 AAACAATTCATATTTCCACT  28 1453 1249634 N/A N/A 200069 200088 AATGATACAATATCAAGTCA  34 1454 1249660 N/A N/A 200605 200624 AACACATTTAACATATGGCA  21 1455 1249686 N/A N/A 202206 202225 CACTACTGCTTCATTAAGCA  33 1456 1249712 N/A N/A 202885 202904 GTTTGTTTCCATTTCCCTTA  18 1457 1249738 N/A N/A 203592 203611 TCATGGTAAACATTTATTTA  47 1458 1249764 N/A N/A 204785 204804 ATCTTCTAATAAATAAGCAA  26 1459 1249790 N/A N/A 206708 206727 AAAGGAGCTTAAATTAGCAA  37 1460 1249816 N/A N/A 208492 208511 GCTTCTTTCCTTAATAAAAT  52 1461 1249842 N/A N/A 210037 210056 CAACATATTTACAATAGTGC  15 1462 1249868 N/A N/A 212791 212810 GTCAGTTCATCAATTTCTAC  19 1463 1249894 N/A N/A 215499 215518 GACTAATTAATTACAAAGTA  56 1464 1249920 N/A N/A 217027 217046 CTCATTATTTTTAAAAGGCC  18 1465 1249946 N/A N/A 222608 222627 ATTATTTTATAAACTATATC  76 1466 1249972 N/A N/A 226988 227007 ACTATTATCACTATTTGCTT  25 1467 1249998 N/A N/A 230339 230358 ATGATGTTTCTTACTACTTT  20 1468 1250024 N/A N/A 232977 232996 GTAAAATCAAAATAATTACT  77 1469 1250050 N/A N/A 235246 235265 ATACCTTTTTCCTAAAGCCA  18 1470 1250076 N/A N/A 236690 236709 AAAAATAATCCTAATATCTT  77 1471 1250102 N/A N/A 239772 239791 AAAGATTTCATAATATTTCT  52 1472 1250128 N/A N/A 242844 242863 AGCTGCTTCTCTCTACATCA  36 1473 1250154 N/A N/A 244835 244854 ATAAATCTCCTTTCTATTCC  80 1474 1250180 N/A N/A 247615 247634 TACTTATTTTTAAACATTAT  75 1475 1250206 N/A N/A 252010 252029 AAGGATTATTTAACTATTTT  64 1476 1250232 4782 4801 254150 254169 TTCTTTGAACCCAGTTTTTT  36 1477 255543 255562 1250258 N/A N/A 255513 255532 TCCCTCTTTTCCTGTGTTTC  26 1478 255622 255641 1250284 N/A N/A 257537 257556 GGTCTTAATTTTAATATCAC  27 1479 1250308 N/A N/A 260417 260436 TTCCAATTATTTAAGAGGTC  39 1480

TABLE 21 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  14 227 1248343  155  174 112568 112587 ATAACAGTCTCCAATGCAAT  59 1481 1248369  563  582 170034 170053 GAGAGATTGCTTTCCCTTTA   8 1482 1248395 1176 1195 183523 183542 GTAGTACCATTCCCATCCAA  16 1483 1248421 1824 1843 188633 188652 CTGTCATTTTTCTCTTCTTC  24 1484 1248447 2461 2480 204363 204382 ATTAGCAAATTTATACCAGC   5 1485 1248473 2805 2824 215434 215453 AGAACTGACAATCCTTCCAC  50 1486 1248499† 3842 3861 240260 240279 ACCAGAGTTTCCCTTTGCCT   3 1487 1248525 4367 4386 247801 247820 TGTAATTAATACAATGGTAA  27 1488 1248550 5887 5906 262415 262434 TCGAAGGGCATCCATCTCTC  47 1489 1248576 6291 6310 262819 262838 TTCTTGGTTTCTTTTTACTT  29 1490 1248602 7185 7204 263713 263732 TATCAAAAATGTGATAGTCA  53 1491 1248627 7352 7371 263880 263899 AATTGACATATACTATGTCA  41 1492 1248653 7480 7499 264008 264027 TTGCAAACTATACTTACTGT  48 1493 1248678 7631 7650 264159 264178 TGCTTCACTTTACCACTGAT  26 1494 1248703 7908 7927 264436 264455 GTGACATCCACCTGAAGATA  71 1495 1248728 8272 8291 264800 264819 TCCCATATTATATCTGATAC  25 1496 1248754 8415 8434 264943 264962 GCATTTCACCAACACACTAC  26 1497 1248780 8561 8580 265089 265108 CATGATAGAAATCTACCTTT  69 1498 1248806 8670 8689 265198 265217 ATCCAATACACTCTTCTTAA  51 1499 1248830 N/A N/A 113497 113516 GTTATTCTAATAATAATCAA  97 1500 1248856 N/A N/A 115905 115924 ATACTTCATCTTACAAACAA  70 1501 1248882 N/A N/A 121980 121999 TTTTATAACACTAATATGCA  80 1502 1248908 N/A N/A 125404 125423 TTTGTTCATCTTAAATTTAA  82 1503 1248934 N/A N/A 128494 128513 TAAACCATAGAGCCATATTT  71 1504 128537 128556 128580 128599 1248959 N/A N/A 139041 139060 AAGTTCAAAATCATATTCTT  76 1505 1248985 N/A N/A 143393 143412 GATACATATTTAAATTACAA  72 1506 1249011 N/A N/A 145985 146004 ACCATAATTCCTATAATTCT  72 1507 1249037 N/A N/A 146782 146801 ATTTTTCTCACTCCCAACCA  63 1508 1249063 N/A N/A 150453 150472 ATTAAATATTTCCTTTGCTT  71 1509 1249089 N/A N/A 155899 155918 CCTCTCTCTCTCATACACTA  57 1510 1249115 N/A N/A 158194 158213 CCCTGGTTCCATCTTCATCT  72 1511 1249141 N/A N/A 163641 163660 AGCAATATACCAACTTGTTA  69 1512 1249167 N/A N/A 170174 170193 GCTCAATAACTTGGTCAAAG   7 1513 1249193 N/A N/A 171686 171705 TAGATCATAATTTATAATCA  44 1514 1249219 N/A N/A 172472 172491 TAGAGACTTTTTAAAATCTA  37 1515 1249245 N/A N/A 173376 173395 TTCTTCTTCCAAACACACAC  25 1516 1249271 N/A N/A 175253 175272 TTGTTTAATTTTAATATGAA  85 1517 1249297 N/A N/A 176728 176747 GGGTCAAGTTTTTACGCTTG   6 1518 1249323 N/A N/A 177580 177599 ATGATCTTCTCAACTACTCT  23 1519 1249349 N/A N/A 178233 178252 TCCTGCTAATTACTTACTCC  14 1520 1249375 N/A N/A 179155 179174 AACTTATTTTCTACTTTACA  60 1521 1249401 N/A N/A 180073 180092 TGGTTTCACCCTATCCCACT  10 1522 1249427 N/A N/A 180778 180797 TGCACTACCATGCCTTCACC  20 1523 1249453 N/A N/A 183580 183599 TTACTTTTATCCTCAATATA  49 1524 1249479 N/A N/A 183896 183915 ACTACTGACTTATTTATTAA  56 1525 1249505 N/A N/A 184866 184885 TTTTTCACAATATTGAACAA  54 1526 1249531 N/A N/A 185678 185697 ATAATAACAATTACAAGCAC  65 1527 1249557 N/A N/A 187239 187258 AATAACTTCTTAATAACCAA  55 1528 1249583 N/A N/A 189876 189895 TCAAAGATCATAATAACTTT  51 1529 1249609 N/A N/A 191337 191356 TTTCAAAAAAATCCAGATTA  64 1530 1249635 N/A N/A 200099 200118 ATTTTACTGTTATTTAGTAA  65 1531 1249661 N/A N/A 200612 200631 ACAAATTAACACATTTAACA  86 1532 1249687 N/A N/A 202217 202236 TTTTGCTTATCCACTACTGC  23 1533 1249713 N/A N/A 202887 202906 CAGTTTGTTTCCATTTCCCT  10 1534 1249739 N/A N/A 203609 203628 ATATAATTCATACATTTTCA  64 1535 1249765 N/A N/A 204849 204868 AGGTTCTTAAAAATATGTCA  26 1536 1249791 N/A N/A 206733 206752 TGCTATTCTTTATCTAGTTT  22 1537 1249817 N/A N/A 208495 208514 AAGGCTTCTTTCCTTAATAA  21 1538 1249843 N/A N/A 210042 210061 TTGCTCAACATATTTACAAT  29 1539 1249869 N/A N/A 212792 212811 AGTCAGTTCATCAATTTCTA  20 1540 1249895 N/A N/A 215502 215521 GAAGACTAATTAATTACAAA  43 1541 1249921 N/A N/A 217110 217129 TTTTGTTTCTCCTTAAGGAA  46 1542 1249947 N/A N/A 222612 222631 AATGATTATTTTATAAACTA  96 1543 1249973 N/A N/A 227094 227113 GTTCTTGACACCTTATTTTA  28 1544 1249999 N/A N/A 230394 230413 CCTCATTTTTTCTTTAATTA  34 1545 1250025 N/A N/A 233210 233229 TAACTTCCTATTAAATTTTT  81 1546 1250051 N/A N/A 235281 235300 TTAGTGCACTACCTTAGTTC  30 1547 1250077 N/A N/A 236707 236726 GTATATCAAATTACTAGAAA  58 1548 1250103 N/A N/A 239809 239828 CTATTTCCCATCTTTATTAT  53 1549 1250129 N/A N/A 242906 242925 GTAATTTTTAAATTTTGGTC  45 1550 1250155 N/A N/A 244845 244864 TGATCTCTAAATAAATCTCC  76 1551 1250181 N/A N/A 247616 247635 TTACTTATTTTTAAACATTA  71 1552 1250207 N/A N/A 252011 252030 AAAGGATTATTTAACTATTT  54 1553 1250233 4783 4802 254151 254170 TTTCTTTGAACCCAGTTTTT  36 1554 255544 255563 1250259 N/A N/A 255514 255533 CTCCCTCTTTTCCTGTGTTT  37 1555 255623 255642 1250285 N/A N/A 257829 257848 GTTTATCTGTCTACTATTCT  50 1556 1250309 N/A N/A 260619 260638 ATCTTTTGCATTCCTAGGAC  36 1557

TABLE 22 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  15  227 1248341  145  164 112558 112577 CCAATGCAATTCTTCAGAAT  40 1558 1248367  560  579 170031 170050 AGATTGCTTTCCCTTTATTC  16 1559 1248393 1172 1191 183519 183538 TACCATTCCCATCCAATGAA  17 1560 1248419 1821 1840 188630 188649 TCATTTTTCTCTTCTTCTCC  32 1561 1248445 2459 2478 204361 204380 TAGCAAATTTATACCAGCAT   9 1562 1248471 2801 2820 215430 215449 CTGACAATCCTTCCACATTT  39 1563 1248497† 3830 3849 240248 240267 CTTTGCCTTCTTCTATGCTT   3 1564 1248523 4320 4339 247754 247773 ATGATACTGAATATTAGCCA  10 1565 1248548 4944 4963 259860 259879 ATGTTTGTCATTTCTTGACT  19 1566 1248574 6286 6305 262814 262833 GGTTTCTTTTTACTTTTTAC  19 1567 1248600 7056 7075 263584 263603 ACATGTACATTTAATGGGTT  63 1568 1248625 7338 7357 263866 263885 ATGTCAACCTTACCAAGAGC  33 1569 1248651 7440 7459 263968 263987 AGTAGTGTGCTTAAATCATC  29 1570 1248676 7628 7647 264156 264175 TTCACTTTACCACTGATATA  52 1571 1248701 7896 7915 264424 264443 TGAAGATACTTTTAATTTCT  40 1572 1248726 8231 8250 264759 264778 AATAAGATCTATCTGTGTAA  40 1573 1248752 8411 8430 264939 264958 TTCACCAACACACTACAAGT  53 1574 1248778 8559 8578 265087 265106 TGATAGAAATCTACCTTTAA  62 1575 1248804 8667 8686 265195 265214 CAATACACTCTTCTTAATTA  75 1576 1248828 N/A N/A 113400 113419 TTCCACTCTTTAACACAGAT  59 1577 1248854 N/A N/A 115793 115812 GCATTTTCAAACCTTCCTTC  61 1578 1248880 N/A N/A 119139 119158 TAATTTGAATCCATATTTTA  89 1579 1248906 N/A N/A 125320 125339 TGATATATTTATACTAGTTA  72 1580 1248932 N/A N/A 128491 128510 ACCATAGAGCCATATTTTAA  67 1581 128534 128553 128577 128596 1248957 N/A N/A 134774 134793 TCCTTTTTTTTAACCATCTA  62 1582 1248983 N/A N/A 142796 142815 CACTTGATTTTAATAAACAT  63 1583 1249009 N/A N/A 145961 145980 CTTCAGTCTACATTTTGCCC  52 1584 1249035 N/A N/A 146646 146665 ATCATAATCACAAATTATAA  79 1585 1249061 N/A N/A 150330 150349 ATAAGCTCTTTAACATTTTA  70 1586 1249087 N/A N/A 155833 155852 TTGGATCCAATCATTTCTCA  75 1587 1249113 N/A N/A 158161 158180 TGACCAACATTCTTTAGATA  79 1588 1249139 N/A N/A 163516 163535 TCTACTTTTTTTAATAAAAA  93 1589 1249165 N/A N/A 169893 169912 GTGTATAACATAATAATTAC  22 1590 1249191 V/A N/A 171609 171628 ATCTTTTTCCCCACATGCTA  32 1591 1249217 N/A N/A 172396 172415 ATCAACAGCTCAACTTGGCA  14 1592 1249243 N/A N/A 173288 173307 TTACAAGAATATCTACCACA  96 1593 1249269 N/A N/A 175236 175255 GAACAAACTCCTATTTGCCA  15 1594 1249295 N/A N/A 176726 176745 GTCAAGTTTTTACGCTTGTG  15 1595 1249321 N/A N/A 177530 177549 ATATTATTCACCATTATAGC  23 1596 1249347 N/A N/A 178167 178186 CCTATGAGAAATCTTAGATT  24 1597 1249373 N/A N/A 178822 178841 GCCTTATCTCCCTTTTCCAT  28 1598 1249399 N/A N/A 179990 180009 AAAACCAAAACAACTATTTA  69 1599 1249425 N/A N/A 180775 180794 ACTACCATGCCTTCACCACC  21 1600 1249451 N/A N/A 182143 182162 GTAGAATTAAATCAGAGTTA  31 1601 1249477 N/A N/A 183854 183873 TGTCTACCAAATAAACATTT  34 1602 1249503 N/A N/A 184852 184871 GAACAAATATCAATATATAA  79 1603 1249529 N/A N/A 185640 185659 AGCTATACATTTATTAATCC  14 1604 1249555 N/A N/A 186607 186626 ACACTGGCTATAATTAGGTT  76 1605 1249581 N/A N/A 189864 189883 ATAACTTTTTCTATTGCTAT  36 1606 1249607 N/A N/A 191230 191249 TTCATATTTCCACTTACTCT  32 1607 1249633 N/A N/A 200026 200045 GAAGTGTTTTTTCATCATTA   9 1608 1249659 N/A N/A 200553 200572 CCAAAGTCTTTATTTTGGCA  12 1609 1249685 N/A N/A 201862 201881 GTCAGTTTTCATTCTAGATA   7 1610 1249711 N/A N/A 202881 202900 GTTTCCATTTCCCTTAATAC   8 1611 1249737 N/A N/A 203585 203604 AAACATTTATTTAAATGTAT  85 1612 1249763 N/A N/A 204697 204716 TTTTTGTTATTTAAAAGGGA  65 1613 1249789 N/A N/A 206546 206565 TCTTATTGACTCATTGGTTA  23 1614 1249815 N/A N/A 208460 208479 TTGTTGAAAATTAATTTAAC  68 1615 1249841 N/A N/A 210003 210022 TTTGTTTATTCTAACAATTT  70 1616 1249867 N/A N/A 212761 212780 TGTGACATTTTTACTGGGAT  12 1617 1249893 N/A N/A 215215 215234 GCAACTTAATTTACTCCCAA  11 1618 1249919 N/A N/A 217026 217045 TCATTATTTTTAAAAGGCCA  27 1619 1249945 N/A N/A 222578 222597 TACATCACAATCTAAATTAA  85 1620 1249971 N/A N/A 226415 226434 CACTGATAATTTATTCCTAA  42 1621 1249997 N/A N/A 230321 230340 TTGTGATATTTAACAATGTA  12 1622 1250023 N/A N/A 232975 232994 AAAATCAAAATAATTACTCA  73 1623 1250049 N/A N/A 235244 235263 ACCTTTTTCCTAAAGCCAAA  27 1624 1250075 N/A N/A 236686 236705 ATAATCCTAATATCTTTGTC  28 1625 1250101 N/A N/A 239406 239425 GTTTGCTTTAAATCTGGCCA  16 1626 1250127 N/A N/A 242772 242791 TGGAATGCATCCTCTAGTAA  39 1627 1250153 N/A N/A 244751 244770 ATGTAATTCTTCAATAGCTT  19 1628 1250179 N/A N/A 247606 247625 TTAAACATTATTAAAAGAAC 111 1629 1250205 N/A N/A 251855 251874 CTGATGCAATTTACTAATTA  40 1630 1250231 4781 4800 254149 254168 TCTTTGAACCCAGTTTTTTC  27 1631 255542 255561 1250257 N/A N/A 255512 255531 CCCTCTTTTCCTGTGTTTCA  19 1632 255621 255640 1250283 N/A N/A 257536 257555 GTCTTAATTTTAATATCACC  19 1633 1250307 N/A N/A 260292 260311 GTACAAGACTATTCTACCAA  41 1634

TABLE 23 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  18 227 1248344  156  175 112569 112588 TATAACAGTCTCCAATGCAA  83 1635 1248370  564  583 170035 170054 CGAGAGATTGCTTTCCCTTT  15 1636 1248396 1178 1197 183525 183544 AAGTAGTACCATTCCCATCC  10 1637 1248422 1828 1847 188637 188656 GACTCTGTCATTTTTCTCTT  23 1638 1248448 2463 2482 204365 204384 ATATTAGCAAATTTATACCA  48 1639 1248474 3021 3040 217735 217754 GGGAGTTCACAATCATTGGA  24 1640 1248500† 3853 3872 240271 240290 CCTCAAATTCCACCAGAGTT   7 1641 1248526 4368 4387 247802 247821 GTGTAATTAATACAATGGTA  15 1642 1248551 5949 5968 262477 262496 GTAATGGGCTCATAAGAGAC  55 1643 1248577 6347 6366 262875 262894 TTGACACAAACACATCACCA  36 1644 1248603 7189 7208 263717 263736 CACTTATCAAAAATGTGATA  61 1645 1248628 7353 7372 263881 263900 AAATTGACATATACTATGTC 103 1646 1248654 7483 7502 264011 264030 AGCTTGCAAACTATACTTAC  35 1647 1248679 7632 7651 264160 264179 TTGCTTCACTTTACCACTGA  30 1648 1248704 7929 7948 264457 264476 CAGAAACTAACAATAGTGAC  53 1649 1248729 8273 8292 264801 264820 ATCCCATATTATATCTGATA  35 1650 1248755 8416 8435 264944 264963 TGCATTTCACCAACACACTA  34 1651 1248781 8570 8589 265098 265117 TTATTTTTACATGATAGAAA  71 1652 1248807 8674 8693 265202 265221 AGTTATCCAATACACTCTTC  49 1653 1248831 N/A N/A 113499 113518 CTGTTATTCTAATAATAATC  70 1654 1248857 N/A N/A 116126 116145 AACCTGTTTTTAAATAGGTG  79 1655 1248883 N/A N/A 121986 122005 GTTTGATTTTATAACACTAA  57 1656 1248909 N/A N/A 125406 125425 GTTTTGTTCATCTTAAATTT  79 1657 1248935 N/A N/A 128496 128515 GTTAAACCATAGAGCCATAT  61 1658 128539 128558 128582 128601 1248960 N/A N/A 139439 139458 TACTCATCTTCATCTTCTTT  73 1659 1248986 N/A N/A 143428 143447 ATTATAAATTATCAATGTTA  73 1660 1249012 N/A N/A 146106 146125 CCAAAATGTTTATTTAGCAT  63 1661 1249038 N/A N/A 147189 147208 TTAATATTATTAAATATCAA 107 1662 1249064 N/A N/A 151067 151086 GTTTAAATCTCAAATACATT  63 1663 1249090 N/A N/A 155932 155951 GGTGAAAAACCTTACAGCCA  61 1664 1249116 N/A N/A 158348 158367 CAATTGTTCCATCTTTGTCA  78 1665 1249142 N/A N/A 163695 163714 GTGTCAACTTCAATTATCAA  50 1666 1249168 N/A N/A 170176 170195 TAGCTCAATAACTTGGTCAA  24 1667 1249194 N/A N/A 171689 171708 TAATAGATCATAATTTATAA  79 1668 1249220 N/A N/A 172505 172524 ACATCTGAAATATAACACTT  58 1669 1249246 N/A N/A 173377 173396 TTTCTTCTTCCAAACACACA  58 1670 1249272 N/A N/A 175319 175338 CAGTGCATATTTCTGAGCCA  15 1671 1249298 N/A N/A 176730 176749 TAGGGTCAAGTTTTTACGCT  11 1672 1249324 N/A N/A 177583 177602 ATGATGATCTTCTCAACTAC  29 1673 1249350 N/A N/A 178247 178266 ATCTACCCCTCCATTCCTGC  45 1674 1249376 N/A N/A 179219 179238 AATATTCTCCACTTTCCTCC  34 1675 1249402 N/A N/A 180164 180183 CTCCTTCAACTTAATGGCCC  14 1676 1249428 N/A N/A 180779 180798 ATGCACTACCATGCCTTCAC  11 1677 1249454 N/A N/A 183583 183602 ATCTTACTTTTATCCTCAAT  30 1678 1249480 N/A N/A 183968 183987 AACCAAATAGGGCCAAATTA  38 1679 1249506 N/A N/A 184869 184888 AGATTTTTCACAATATTGAA  48 1680 1249532 N/A N/A 185688 185707 CATGATCCCAATAATAACAA  33 1681 1249558 N/A N/A 187243 187262 AAGTAATAACTTCTTAATAA  78 1682 1249584 N/A N/A 189912 189931 ATTTGAATACCAACAACCCT  43 1683 1249610 N/A N/A 191393 191412 CTTATCACAAATAAATAATA  82 1684 1249636 N/A N/A 200126 200145 ATAATAGAATCCATGAGTTA  76 1685 1249662 N/A N/A 200617 200636 AAGTCACAAATTAACACATT  70 1686 1249688 N/A N/A 202385 202404 GGGTTATCCACATAGAATCA  31 1687 1249714 N/A N/A 202947 202966 ATTTCCACTAAAAATAGATT  60 1688 1249740 N/A N/A 203612 203631 TACATATAATTCATACATTT  60 1689 1249766 N/A N/A 205035 205054 TCTAAATTTAATATTGCTAA  67 1690 1249792 N/A N/A 206885 206904 GTGTCTTTCCTCTTTTTTTC  13 1691 1249818 N/A N/A 208552 208571 GTTCAATTCCATTCTTTCAT  22 1692 1249844 N/A N/A 210056 210075 TTTTTTCCTTTAAATTGCTC  49 1693 1249870 N/A N/A 213035 213054 AAACACTTCCTTTCTTCTAT  48 1694 1249896 N/A N/A 215503 215522 TGAAGACTAATTAATTACAA  84 1695 1249922 N/A N/A 217302 217321 GATGAATTATTTATTTGTCA  24 1696 1249948 N/A N/A 222759 222778 ATATATGACTACCTTAGCTA  61 1697 1249974 N/A N/A 227123 227142 TTGCTTTCCATCATTAGTTT  43 1698 1250000 N/A N/A 230617 230636 AAGGAATTACATTAATATAA  54 1699 1250026 N/A N/A 233213 233232 ACATAACTTCCTATTAAATT  75 1700 1250052 N/A N/A 235333 235352 TCTTATTTAAATCACATTAA  75 1701 1250078 N/A N/A 236728 236747 TTTCTTATTTTAATTTATCA  79 1702 1250104 N/A N/A 239810 239829 ACTATTTCCCATCTTTATTA  47 1703 1250130 N/A N/A 243053 243072 ATGATTTCTTAAAAAAGGAA  70 1704 1250156 N/A N/A 246375 246394 CTGCTCTCAATAATAATTCT  25 1705 1250182 N/A N/A 247629 247648 CAACAACAAATATTTACTTA  62 1706 1250208 N/A N/A 252051 252070 TTAACTTTCTCAAATAATGT  75 1707 1250234 4784 4803 254152 254171 GTTTCTTTGAACCCAGTTTT  20 1708 255545 255564 1250260 N/A N/A 255515 255534 CCTCCCTCTTTTCCTGTGTT  30 1709 255624 255643 1250286 N/A N/A 257905 257924 CTTACTTCCACCCTCTGATA  65 1710 1250310 N/A N/A 260671 260690 CTCATTTAATATCTTATACA  63 1711

TABLE 24 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  14  227 1248345  161  180 112574 112593 TTGAATATAACAGTCTCCAA  60 1712 1248371  565  584 170036 170055 TCGAGAGATTGCTTTCCCTT  12 1713 1248397 1179 1198 183526 183545 AAAGTAGTACCATTCCCATC  26 1714 1248423 1830 1849 188639 188658 CGGACTCTGTCATTTTTCTC  22 1715 1248449 2473 2492 204375 204394 AATCAAACACATATTAGCAA  20 1716 1248475 3292 3311 227286 227305 CTGCATCCTTCCCACAGCAA  16 1717 1248501† 3858 3877 240276 240295 GTTTTCCTCAAATTCCACCA  10 1718 1248527 4369 4388 247803 247822 GGTGTAATTAATACAATGGT  23 1719 1248552 6033 6052 262561 262580 ACTTTTTGCTTCAAGAGGTA  71 1720 1248578 6406 6425 262934 262953 CCTTAAGTATACATTTGTAA  65 1721 1248604 7191 7210 263719 263738 GACACTTATCAAAAATGTGA  31 1722 1248629 7357 7376 263885 263904 TTTTAAATTGACATATACTA  75 1723 1248655 7484 7503 264012 264031 AAGCTTGCAAACTATACTTA  44 1724 1248680 7634 7653 264162 264181 ATTTGCTTCACTTTACCACT  38 1725 1248705 7930 7949 264458 264477 ACAGAAACTAACAATAGTGA  49 1726 1248730 8277 8296 264805 264824 TGGGATCCCATATTATATCT  61 1727 1248756 8417 8436 264945 264964 ATGCATTTCACCAACACACT  48 1728 1248782 8574 8593 265102 265121 TAGATTATTTTTACATGATA  86 1729 1248808 8675 8694 265203 265222 TAGTTATCCAATACACTCTT  66 1730 1248832 N/A N/A 113615 113634 AGGCATTTAAAAACAATCTT  58 1731 1248858 N/A N/A 116897 116916 TTATCTTTTCCTAATAGAAA  79 1732 1248884 N/A N/A 122656 122675 TTGGTGATTTATATAAACTA  68 1733 1248910 N/A N/A 125522 125541 TGCTCTTTTTTAAATAAAAA 110 1734 1248936 N/A N/A 128497 128516 AGTTAAACCATAGAGCCATA  77 1735 128540 128559 1248961 N/A N/A 139746 139765 GATTTATTTTTTACCTATTA  86 1736 1248987 N/A N/A 143434 143453 TTAAATATTATAAATTATCA  73 1737 1249013 N/A N/A 146189 146208 TAGACTATTTTCACTAGTAC  69 1738 1249039 N/A N/A 147200 147219 TCTTCTTTTTCTTAATATTA  79 1739 1249065 N/A N/A 151070 151089 GCAGTTTAAATCTCAAATAC  53 1740 1249091 N/A N/A 155966 155985 TTTATGTATTCAACAAATAA  74 1741 1249117 N/A N/A 158526 158545 CTGAAAGTTTCCTTTTCCTA  75 1742 1249143 N/A N/A 163721 163740 CAATATTTCATAAATCTCTA  82 1743 1249169 N/A N/A 170177 170196 GTAGCTCAATAACTTGGTCA  16 1744 1249195 N/A N/A 171690 171709 ATAATAGATCATAATTTATA  84 1745 1249221 N/A N/A 172534 172553 CTTTTGTTATATCTCTGCTC  25 1746 1249247 N/A N/A 173422 173441 GTAACACTTATCACTAGCTC  53 1747 1249273 N/A N/A 175434 175453 GAGGAGTTTTTAACCTATAT   8 1748 1249299 N/A N/A 176732 176751 ACTAGGGTCAAGTTTTTACG  25 1749 1249325 N/A N/A 177584 177603 AATGATGATCTTCTCAACTA  52 1750 1249351 N/A N/A 178255 178274 ATCTTTTAATCTACCCCTCC  44 1751 1249377 N/A N/A 179271 179290 CTGTATTTTCCTACTAGGCT  14 1752 1249403 N/A N/A 180170 180189 GTAAGTCTCCTTCAACTTAA  13 1753 1249429 N/A N/A 180780 180799 TATGCACTACCATGCCTTCA  19 1754 1249455 N/A N/A 183612 183631 ACTAAACAACTTAATGGTTT  33 1755 1249481 N/A N/A 183970 183989 TCAACCAAATAGGGCCAAAT  26 1756 1249507 N/A N/A 184898 184917 GATAAACTAATAAATATATA  81 1757 1249533 N/A N/A 185689 185708 GCATGATCCCAATAATAACA  20 1758 1249559 N/A N/A 187247 187266 AATAAAGTAATAACTTCTTA  78 1759 1249585 N/A N/A 189967 189986 TCTTCATAGGCAACTTGATA  35 1760 1249611 N/A N/A 191396 191415 TAGCTTATCACAAATAAATA  89 1761 1249637 N/A N/A 200160 200179 GAGGCTAAATATAAAAAAAA  75 1762 1249663 N/A N/A 200618 200637 AAAGTCACAAATTAACACAT  34 1763 1249689 N/A N/A 202409 202428 GCCACATCTCCATTATTCCT  36 1764 1249715 N/A N/A 202959 202978 ATTGTTTTTAAAATTTCCAC  42 1765 1249741 N/A N/A 203613 203632 ATACATATAATTCATACATT  88 1766 1249767 N/A N/A 205036 205055 TTCTAAATTTAATATTGCTA  67 1767 1249793 N/A N/A 206901 206920 CTACTTCTAATAATTAGTGT  68 1768 1249819 N/A N/A 208582 208601 CTTAATTTTTATATATGTTA  90 1769 1249845 N/A N/A 210150 210169 TGTGTACTTTTCAATTATAA  36 1770 1249871 N/A N/A 213230 213249 GTCTGTTTTCCAATAAATTT  28 1771 1249897 N/A N/A 215560 215579 GTGTATTCAAATAATATTAT  38 1772 1249923 N/A N/A 217353 217372 GTAATTTTATTAACAGGGCA  34 1773 1249949 N/A N/A 222886 222905 GACACCTTTCCCATTTTTCC  35 1774 1249975 N/A N/A 227145 227164 TCAAAACATTCTATTGCTTC  99 1775 1250001 N/A N/A 230638 230657 AACAATCATTCAAAATCACA  87 1776 1250027 N/A N/A 233343 233362 TTTCTGCTTTAATAATACTA  31 1777 1250053 N/A N/A 235337 235356 TTTCTCTTATTTAAATCACA  37 1778 1250079 N/A N/A 236729 236748 ATTTCTTATTTTAATTTATC  72 1779 1250105 N/A N/A 239907 239926 GTTGGTATTTCCATCCTGTC  35 1780 1250131 N/A N/A 243054 243073 GATGATTTCTTAAAAAAGGA  34 1781 1250157 N/A N/A 246378 246397 AGTCTGCTCTCAATAATAAT  49 1782 1250183 N/A N/A 247961 247980 AAGTGATTACTTACTACTTG  47 1783 1250209 N/A N/A 252054 252073 TCTTTAACTTTCTCAAATAA  55 1784 1250235 4785 4804 254153 254172 GGTTTCTTTGAACCCAGTTT  11 1785 255546 255565 1250261 N/A N/A 255516 255535 TCCTCCCTCTTTTCCTGTGT  37 1786 255625 255644 1250287 N/A N/A 258046 258065 AACTAGATTTCTATTACTCC  51 1787 1250311 N/A N/A 260672 260691 CCTCATTTAATATCTTATAC  49 1788

TABLE 25 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910088 8676 8695 265204 265223 GTAGTTATCCAATACACTCT  44  120  910184 N/A N/A 128500 128519 TGGAGTTAAACCATAGAGCC  78  136 128543 128562  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  17  227 1248346  164  183 112577 112596 GTGTTGAATATAACAGTCTC  62 1789 1248372  567  586 170038 170057 AATCGAGAGATTGCTTTCCC  24 1790 1248398 1180 1199 183527 183546 GAAAGTAGTACCATTCCCAT  17 1791 1248424 1869 1888 188678 188697 AAACCTTTTCTTCTTATGCT  28 1792 1248450 2474 2493 204376 204395 AAATCAAACACATATTAGCA  39 1793 1248476 3304 3323 227298 227317 ATCGATTCCTTTCTGCATCC  17 1794 1248502† 3859 3878 240277 240296 TGTTTTCCTCAAATTCCACC  11 1795 1248528 4389 4408 247823 247842 ACATCAAACATCTCTCCAGT  32 1796 1248553 6041 6060 262569 262588 CCTTTTTAACTTTTTGCTTC  53 1797 1248579 6472 6491 263000 263019 CTATTTCTCCAGTTTACTGA  58 1798 1248605 7192 7211 263720 263739 GGACACTTATCAAAAATGTG  40 1799 1248630 7371 7390 263899 263918 AGCAGACTTTTATTTTTTAA  34 1800 1248656 7505 7524 264033 264052 TTACATCATATTACCTGTTG  36 1801 1248681 7635 7654 264163 264182 AATTTGCTTCACTTTACCAC  42 1802 1248706 7934 7953 264462 264481 AGGAACAGAAACTAACAATA  42 1803 1248731 8278 8297 264806 264825 CTGGGATCCCATATTATATC  40 1804 1248757 8418 8437 264946 264965 CATGCATTTCACCAACACAC  38 1805 1248783 8587 8606 265115 265134 TTTGTTTTTCAGATAGATTA  55 1806 1248833 N/A N/A 113800 113819 TTTTATAAAATCATTCCCCA  71 1807 1248859 N/A N/A 117256 117275 CTTTCCTTTTCTATTTATTT  36 1808 1248885 N/A N/A 123302 123321 GAGAGCTATTTTAATAGGTC  65 1809 1248911 N/A N/A 125523 125542 ATGCTCTTTTTTAAATAAAA  87 1810 1248962 N/A N/A 139883 139902 TGTCTTGACTTCTCTTGCAA  64 1811 1248988 N/A N/A 143940 143959 ATTGAGTTTTTAATAAGGCT  63 1812 1249014 N/A N/A 146203 146222 ATATTAACACTATCTAGACT  59 1813 1249040 N/A N/A 147348 147367 TTTTAATTTTTTCTCCCCTA  70 1814 1249066 N/A N/A 151071 151090 AGCAGTTTAAATCTCAAATA  94 1815 1249092 N/A N/A 155991 156010 AACAGATACATAACAGGACA  98 1816 1249118 N/A N/A 158779 158798 CAGGATTTTTTAATACCACC  61 1817 1249144 N/A N/A 163722 163741 ACAATATTTCATAAATCTCT  84 1818 1249170 N/A N/A 170178 170197 TGTAGCTCAATAACTTGGTC  16 1819 1249196 N/A N/A 171702 171721 GCTTGAAACATAATAATAGA  20 1820 1249222 N/A N/A 172560 172579 GTATCTTAGACTATTAGCCT  14 1821 1249248 N/A N/A 173442 173461 ACACTAATTTATATTTCTTA  79 1822 1249274 N/A N/A 175517 175536 TCTTTGTTATTCTATAGGAA  15 1823 1249300 N/A N/A 176734 176753 TAACTAGGGTCAAGTTTTTA  47 1824 1249326 N/A N/A 177609 177628 TATTATTCCTCTAATGACAA  59 1825 1249352 N/A N/A 178286 178305 TTTGAATTCTAAAACTGAAC 101 1826 1249378 N/A N/A 179455 179474 TTTATTGCTATAACAAACAA  72 1827 1249404 N/A N/A 180196 180215 TATGAAGATCAAATTTGTTA  63 1828 1249430 N/A N/A 180782 180801 TTTATGCACTACCATGCCTT  31 1829 1249456 N/A N/A 183619 183638 TTAGAGAACTAAACAACTTA  79 1830 1249482 N/A N/A 183971 183990 ATCAACCAAATAGGGCCAAA  21 1831 1249508 N/A N/A 184935 184954 GGCAAAGCTCACAAATGTTT  54 1832 1249534 N/A N/A 185691 185710 TTGCATGATCCCAATAATAA  36 1833 1249560 N/A N/A 187312 187331 AAAGCAATTATAATTATCCA  54 1834 1249586 N/A N/A 189969 189988 ATTCTTCATAGGCAACTTGA  32 1835 1249612 N/A N/A 191509 191528 CATTCATTACATAAATGCAT  32 1836 1249638 N/A N/A 200162 200181 TGGAGGCTAAATATAAAAAA  66 1837 1249664 N/A N/A 200620 200639 TCAAAGTCACAAATTAACAC  40 1838 1249690 N/A N/A 202487 202506 CATTCAATTATTCATTCCAA  38 1839 1249716 N/A N/A 202978 202997 GTAAATTAATTTATTGCTTA  61 1840 1249742 N/A N/A 203617 203636 AAACATACATATAATTCATA  68 1841 1249768 N/A N/A 205038 205057 ATTTCTAAATTTAATATTGC  71 1842 1249794 N/A N/A 206911 206930 CTCTTCATTCCTACTTCTAA  80 1843 1249820 N/A N/A 208583 208602 TCTTAATTTTTATATATGTT  79 1844 1249846 N/A N/A 210278 210297 ATTTTTCCTTTTAATTCTCT  56 1845 1249872 N/A N/A 213259 213278 GGACATTTAAATAATAGATA  70 1846 1249898 N/A N/A 215561 215580 AGTGTATTCAAATAATATTA  41 1847 1249924 N/A N/A 220524 220543 ACATACATATACACTTGCCA  32 1848 1249950 N/A N/A 223280 223299 ATTACATATTTTAATTGTTT  84 1849 1249976 N/A N/A 227672 227691 CCTTATTTAAACATTTTTAC  75 1850 1250002 N/A N/A 230675 230694 GCATGGCTTCCACATTATTA  34 1851 1250028 N/A N/A 233370 233389 TTTAGATATTATACTTCCAA  34 1852 1250054 N/A N/A 235344 235363 CCTGTATTTTCTCTTATTTA  30 1853 1250080 N/A N/A 236952 236971 ATAAAATATTTCCTTAGCAT  63 1854 1250106 N/A N/A 239989 240008 TAGCACTACTATAATGGATT  51 1855 1250132 N/A N/A 243091 243110 TTCTATTAAATTTTATGATC  76 1856 1250158 N/A N/A 246379 246398 CAGTCTGCTCTCAATAATAA  46 1857 1250184 N/A N/A 247996 248015 AGACTCATTTTAATTACACA  25 1858 1250210 N/A N/A 252125 252144 ATTATCCTAAACATGTGCAT  33 1859 1250236 4786 4805 254154 254173 TGGTTTCTTTGAACCCAGTT  19 1860 255547 255566 1250262 N/A N/A 255517 255536 ATCCTCCCTCTTTTCCTGTG  47 1861 255626 255645 1250288 N/A N/A 258110 258129 ACATCAAACACTACTTGTTC  57 1862 1250312 N/A N/A 260697 260716 AATCTTCTTATATTTACTTC  71 1863

TABLE 26 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SEQ Compound 1 Start 1 Stop 2 Start 2 Stop SCN2A ID Number Site Site Site Site Sequence (5′ to 3′) (% control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA  26  227 1248347  166  185 112579 112598 ATGTGTTGAATATAACAGTC  68 1864 1248373  568  587 170039 170058 GAATCGAGAGATTGCTTTCC  30 1865 1248399 1182 1201 183529 183548 TTGAAAGTAGTACCATTCCC  26 1866 1248425 1895 1914 188704 188723 GCCTACTTCCTTCCAAGGAA  22 1867 1248451 2496 2515 204398 204417 AACCATGGTTTACAACAGTC  39 1868 1248477 3307 3326 227301 227320 AAAATCGATTCCTTTCTGCA  31 1869 1248503† 3860 3879 240278 240297 ATGTTTTCCTCAAATTCCAC  40 1870 1248529 4391 4410 247825 247844 TTACATCAAACATCTCTCCA  49 1871 1248554 6042 6061 262570 262589 ACCTTTTTAACTTTTTGCTT  45 1872 1248580 6478 6497 263006 263025 TCGATACTATTTCTCCAGTT  33 1873 1248606 7193 7212 263721 263740 AGGACACTTATCAAAAATGT  37 1874 1248631 7372 7391 263900 263919 AAGCAGACTTTTATTTTTTA  43 1875 1248657 7507 7526 264035 264054 AATTACATCATATTACCTGT  37 1876 1248682 7636 7655 264164 264183 CAATTTGCTTCACTTTACCA  63 1877 1248707 7953 7972 264481 264500 GCTTCAATTTAAAAGTGCTA  43 1878 1248732 8279 8298 264807 264826 GCTGGGATCCCATATTATAT  51 1879 1248758 8419 8438 264947 264966 GCATGCATTTCACCAACACA  53 1880 1248784 8588 8607 265116 265135 ATTTGTTTTTCAGATAGATT  71 1881 1248809 8677 8696 265205 265224 AGTAGTTATCCAATACACTC  56 1882 1248834 N/A N/A 113801 113820 ATTTTATAAAATCATTCCCC  79 1883 1248860 N/A N/A 117455 117474 GTCTTCTTCCACATAAAGGT  63 1884 1248886 N/A N/A 123365 123384 GTCTACTCAAACAAACACTA  60 1885 1248912 N/A N/A 126286 126305 AAGAATTTCATAAACTTCAT  87 1886 1248937 N/A N/A 128501 128520 ATGGAGTTAAACCATAGAGC  64 1887 128544 128563 1248963 N/A N/A 139924 139943 GTTTATTCCTCAATATTTTT  75 1888 1248989 N/A N/A 144023 144042 GCACAGTATTTTACTTATCA  74 1889 1249015 N/A N/A 146216 146235 ATAATTTCTATCAATATTAA  78 1890 1249041 N/A N/A 147450 147469 CAGTCATTCCTAATACATTA  56 1891 1249067 N/A N/A 152305 152324 GTCTTCCCTATCTCAACCAA  75 1892 1249093 N/A N/A 156022 156041 TGCATCTTCATTACCATCAA  68 1893 1249119 N/A N/A 161701 161720 CTTCTCTTTTTAACCTGAAT  78 1894 1249145 N/A N/A 163896 163915 GTCACATTCTCATCATATTT  64 1895 1249171 N/A N/A 170180 170199 TGTGTAGCTCAATAACTTGG  24 1896 1249197 N/A N/A 171772 171791 GAACATACAATTATTTTAAA  81 1897 1249223 N/A N/A 172625 172644 ACCTCTAACTTTACTGGGCT  24 1898 1249249 N/A N/A 173459 173478 TGTCACTCCTCCCTTTGACA  36 1899 1249275 N/A N/A 175540 175559 AGAGTATAAAATTATAGGAC  38 1900 1249301 N/A N/A 176818 176837 ATCATTTTAATAAAAGTATA  91 1901 1249327 N/A N/A 177610 177629 ATATTATTCCTCTAATGACA  57 1902 1249353 N/A N/A 178288 178307 ATTTTGAATTCTAAAACTGA  94 1903 1249379 N/A N/A 179465 179484 ACAATTTTTCTTTATTGCTA  41 1904 1249405 N/A N/A 180277 180296 GCAAAATTACTTATTAAGTT  66 1905 1249431 N/A N/A 180926 180945 ATACTTACTCCACATTCTTT  71 1906 1249457 N/A N/A 183621 183640 ATTTAGAGAACTAAACAACT  57 1907 1249483 N/A N/A 183972 183991 CATCAACCAAATAGGGCCAA  17 1908 1249509 N/A N/A 185086 185105 TAGGAAGCATCACTTACCCT 109 1909 1249535 N/A N/A 185714 185733 CCATGTTTCTTAATAGCAAA  41 1910 1249561 N/A N/A 187364 187383 TTGTTAATCATTAATTTCCT  42 1911 1249587 N/A N/A 189970 189989 CATTCTTCATAGGCAACTTG  36 1912 1249613 N/A N/A 191698 191717 AGTTTATATTTTAACTGCCA  25 1913 1249639 N/A N/A 200199 200218 GGTGTTCAAAATATACCTTA  19 1914 1249665 N/A N/A 200622 200641 ATTCAAAGTCACAAATTAAC  65 1915 1249691 N/A N/A 202499 202518 CTAAAATAAAATCATTCAAT  77 1916 1249717 N/A N/A 202983 203002 CCTAAGTAAATTAATTTATT  78 1917 1249743 N/A N/A 203657 203676 AACTCATTTATTACTGGAAA  36 1918 1249769 N/A N/A 205059 205078 TTTAACAAAATTAAATAAAT 106 1919 1249795 N/A N/A 206914 206933 CCTCTCTTCATTCCTACTTC  49 1920 1249821 N/A N/A 208591 208610 ATGACCTATCTTAATTTTTA  67 1921 1249847 N/A N/A 210310 210329 ATATTATCCCATATTATAGT  58 1922 1249873 N/A N/A 213321 213340 CATGTGTATATTACTAGACT  34 1923 1249899 N/A N/A 215633 215652 AGTGAACTTTATTAAAGCTA  35 1924 1249925 N/A N/A 220797 220816 GATCAACCTTCCTATTGTAA  91 1925 1249951 N/A N/A 224068 224087 CATCTATAAAATAAATGTAA 104 1926 1249977 N/A N/A 227766 227785 CAGATATTTTCTATTTTCTT  48 1927 1250003 N/A N/A 230954 230973 TGTTTTTATTTTACTGCCAA  42 1928 1250029 N/A N/A 233409 233428 ATCTAATAAACATCAAGGTA  41 1929 1250055 N/A N/A 235366 235385 ATTTCAAATTATAAAAGACA  81 1930 1250081 N/A N/A 237009 237028 ATGTGGATTTTCTCTAGAAA  23 1931 1250107 N/A N/A 239994 240013 GTTTATAGCACTACTATAAT  52 1932 1250133 N/A N/A 243092 243111 ATTCTATTAAATTTTATGAT  73 1933 1250159 N/A N/A 246419 246438 AAATTCTCCATAAATTTGAC  88 1934 1250185 N/A N/A 248151 248170 CTGTTTTCCATAAAAGCTAT  37 1935 1250211 N/A N/A 252236 252255 TTCATTTTCATCACTATATA  53 1936 1250237 4787 4806 254155 254174 GTGGTTTCTTTGAACCCAGT  31 1937 255548 255567 1250263 N/A N/A 255611 255630 CTGTGTTTCATAACAGGCAA  42 1938 1250289 N/A N/A 258117 258136 TTTTTGGACATCAAACACTA  92 1939 1250313 N/A N/A 260701 260720 CTTAAATCTTCTTATATTTA  95 1940

TABLE 27 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SCN2A SEQ Compound 1 Start 1 Stop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA 24 227 1248348 193 212 112606 112625 ATGTAAATCATAACACAGAA 90 1941 1248374 569 588 170040 170059 TGAATCGAGAGATTGCTTTC 35 1942 1248400 1196 1215 183543 183562 TGCTCACTGTCCTATTGAAA 27 1943 1248426 1922 1941 188731 188750 GAGAAGAAAATCTCTTTTCA 55 1944 1248452 2504 2523 204406 204425 TCACCTTTAACCATGGTTTA 67 1945 1248478 3323 3342 227317 227336 GTATTTTTCTTTTAACAAAA 49 1946 1248504† 3863 3882 240281 240300 AGCATGTTTTCCTCAAATTC 38 1947 1248530 4392 4411 247826 247845 CTTACATCAAACATCTCTCC 41 1948 1248555 6046 6065 262574 262593 TGATACCTTTTTAACTTTTT 61 1949 1248581 6592 6611 263120 263139 TTACATAAAAATTTAACTTC 87 1950 1248607 7195 7214 263723 263742 AAAGGACACTTATCAAAAAT 69 1951 1248632 7384 7403 263912 263931 TTACTATTTACAAAGCAGAC 67 1952 1248658 7508 7527 264036 264055 CAATTACATCATATTACCTG 58 1953 1248683 7637 7656 264165 264184 ACAATTTGCTTCACTTTACC 52 1954 1248708 7954 7973 264482 264501 TGCTTCAATTTAAAAGTGCT 44 1955 1248733 8280 8299 264808 264827 AGCTGGGATCCCATATTATA 53 1956 1248759 8420 8439 264948 264967 TGCATGCATTTCACCAACAC 45 1957 1248785 8600 8619 265128 265147 TGTGTTCTTTACATTTGTTT 58 1958 1248810 8678 8697 265206 265225 AAGTAGTTATCCAATACACT 60 1959 1248835 N/A N/A 113871 113890 ATGTAGAACTACAAACTCTA 61 1960 1248861 N/A N/A 117498 117517 ATAAGATTTTTTCATTATTA 76 1961 1248887 N/A N/A 123399 123418 ACTATATCCATATCATTTTA 77 1962 1248913 N/A N/A 126445 126464 CTTTATCTCTCCAAACCATC 84 1963 1248938 N/A N/A 128503 128522 ATATGGAGTTAAACCATAGA 67 1964 128546 128565 1248964 N/A N/A 139945 139964 ACAGATATTTCACCTCATTA 75 1965 1248990 N/A N/A 144248 144267 TCTTTGCTCATAATACCATT 72 1966 1249016 N/A N/A 146217 146236 TATAATTTCTATCAATATTA 75 1967 1249042 N/A N/A 147470 147489 CTAGCATATTCCATTACTTC 71 1968 1249068 N/A N/A 152306 152325 TGTCTTCCCTATCTCAACCA 72 1969 1249094 N/A N/A 156025 156044 CACTGCATCTTCATTACCAT 65 1970 1249120 N/A N/A 161702 161721 CCTTCTCTTTTTAACCTGAA 80 1971 1249146 N/A N/A 165017 165036 CCGTAGCTTCCCTACAGCTA 75 1972 1249172 N/A N/A 170181 170200 ATGTGTAGCTCAATAACTTG 31 1973 1249198 N/A N/A 171775 171794 AAGGAACATACAATTATTTT 56 1974 1249224 N/A N/A 172632 172651 TCTATATACCTCTAACTTTA 68 1975 1249250 N/A N/A 173610 173629 CTTCAGACTTTACCTTCATA 52 1976 1249276 N/A N/A 175562 175581 TTACCATTAATAACTCATTT 41 1977 1249302 N/A N/A 176821 176840 GCTATCATTTTAATAAAAGT 41 1978 1249328 N/A N/A 177620 177639 AGCAGCCCTTATATTATTCC 15 1979 1249354 N/A N/A 178311 178330 TACATATCTTATCAACACTT 55 1980 1249380 N/A N/A 179595 179614 ATGAAAACACTCATAAGTAA 68 1981 1249406 N/A N/A 180349 180368 GCTCATAAAATCCTGAACTA 23 1982 1249432 N/A N/A 180932 180951 ATATTTATACTTACTCCACA 100 1983 1249458 N/A N/A 183643 183662 TCCATTATATATAATATTTA 92 1984 1249484 N/A N/A 183974 183993 TGCATCAACCAAATAGGGCC 15 1985 1249510 N/A N/A 185226 185245 ATCTACACTTATCCTGGCTA 96 1986 1249536 N/A N/A 185715 185734 TCCATGTTTCTTAATAGCAA 26 1987 1249562 N/A N/A 187367 187386 CCTTTGTTAATCATTAATTT 53 1988 1249588 N/A N/A 189971 189990 GCATTCTTCATAGGCAACTT 16 1989 1249614 N/A N/A 191779 191798 ATACTGCTCCTCATTAGCTA 65 1990 1249640 N/A N/A 200200 200219 TGGTGTTCAAAATATACCTT 48 1991 1249666 N/A N/A 200631 200650 GAGACTGAAATTCAAAGTCA 45 1992 1249692 N/A N/A 202500 202519 TCTAAAATAAAATCATTCAA 89 1993 1249718 N/A N/A 203006 203025 AATTAATTCTATAATACTAT 79 1994 1249744 N/A N/A 203683 203702 TTACAAATCAACATTTCACA 60 1995 1249770 N/A N/A 205107 205126 ATACTATATTATAATATCAA 80 1996 1249796 N/A N/A 206945 206964 CTTTTTCTTTCTAAAAGATC 73 1997 1249822 N/A N/A 208673 208692 TCATTGCTTAATAATAGGTC 25 1998 1249848 N/A N/A 210312 210331 TGATATTATCCCATATTATA 47 1999 1249874 N/A N/A 213367 213386 GTGACTTTTCCAAATATTAC 46 2000 1249900 N/A N/A 215699 215718 CTGTTTCCTCCTCTCTATTA 71 2001 1249926 N/A N/A 220846 220865 TCTCAGTTAAATATATTTTA 69 2002 1249952 N/A N/A 224116 224135 TTTCTGTTACCTACTAAGTA 49 2003 1249978 N/A N/A 228224 228243 TGATTCCTCATCAATACCTT 45 2004 1250004 N/A N/A 230955 230974 ATGTTTTTATTTTACTGCCA 36 2005 1250030 N/A N/A 233413 233432 AATGATCTAATAAACATCAA 83 2006 1250056 N/A N/A 235406 235425 GGTGTTTTTTTTAATTGCTT 32 2007 1250082 N/A N/A 237351 237370 AATGCAATAAACTTTAGCCA 54 2008 1250108 N/A N/A 240033 240052 GGCTTTTTAATCATTTGTTT 30 2009 1250134 N/A N/A 243096 243115 AAAAATTCTATTAAATTTTA 89 2010 1250160 N/A N/A 246422 246441 CACAAATTCTCCATAAATTT 55 2011 1250186 N/A N/A 248152 248171 ACTGTTTTCCATAAAAGCTA 39 2012 1250212 N/A N/A 252444 252463 CTGGAGGTAATCATTATCCT 33 2013 1250238 4788 4807 254156 254175 TGTGGTTTCTTTGAACCCAG 16 2014 255549 255568 1250264 N/A N/A 255673 255692 CACAAAATATCAACTAGCTT 61 2015 1250290 N/A N/A 258143 258162 GAGGCTTCTATTACTTCCAA 48 2016 1250314 N/A N/A 260862 260881 ATCTTACCTCTTAATGCTAC 71 2017

TABLE 28 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID ID ID ID NO: NO: NO: NO: 1 1 2 2 SCN2A SEQ Compound Start Stop Start Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) control) NO 910092 8731 8750 265259 265278 GTAACTTTCCACTAGTCTAC 58 432 910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA 27 227 1248349 197 216 112610 112629 AAAAATGTAAATCATAACAC 80 2018 1248375 571 590 170042 170061 ACTGAATCGAGAGATTGCTT 27 2019 1248401 1219 1238 183566 183585 AATATATTCATCCCAGTTAA 57 2020 1248427 2308 2327 199865 199884 TCTCTTTCTTATTTCTGTTT 47 2021 1248453 2505 2524 204407 204426 TTCACCTTTAACCATGGTTT 70 2022 1248479 3363 3382 227357 227376 GCTTTCTGCTTCCTAACAAA 23 2023 1248505† 3864 3883 240282 240301 TAGCATGTTTTCCTCAAATT 29 2024 1248531 4398 4417 247832 247851 ACCACGCTTACATCAAACAT 44 2025 1248556 6047 6066 262575 262594 TTGATACCTTTTTAACTTTT 54 2026 1248582 6593 6612 263121 263140 TTTACATAAAAATTTAACTT 88 2027 1248608 7198 7217 263726 263745 GCCAAAGGACACTTATCAAA 35 2028 1248633 7385 7404 263913 263932 ATTACTATTTACAAAGCAGA 66 2029 1248659 7509 7528 264037 264056 CCAATTACATCATATTACCT 47 2030 1248684 7703 7722 264231 264250 CAAGAAGCTCTTCCTTGTTT 62 2031 1248709 7955 7974 264483 264502 GTGCTTCAATTTAAAAGTGC 43 2032 1248734 8317 8336 264845 264864 ATAACTTCACTACCTGGTTT 50 2033 1248760 8421 8440 264949 264968 CTGCATGCATTTCACCAACA 40 2034 1248786 8601 8620 265129 265148 GTGTGTTCTTTACATTTGTT 66 2035 1248836 N/A N/A 113905 113924 CTGTAATTCTAAAAATCTCC 76 2036 1248862 N/A N/A 117593 117612 TATCACATTCCAATAAATAA 74 2037 1248888 N/A N/A 123415 123434 TTAAAATTTTCTATATACTA 77 2038 1248914 N/A N/A 126502 126521 TTTATGGACATTAAACTTCA 76 2039 1248939 N/A N/A 128505 128524 GGATATGGAGTTAAACCATA 74 2040 128548 128567 1248965 N/A N/A 140046 140065 TTTAAGAACATTAATTCTTT 83 2041 1248991 N/A N/A 144249 144268 GTCTTTGCTCATAATACCAT 67 2042 1249017 N/A N/A 146222 146241 TTAGTTATAATTTCTATCAA 86 2043 1249043 N/A N/A 147483 147502 GTAGCTATATTCACTAGCAT 59 2044 1249069 N/A N/A 152331 152350 TCAGTTTCTTCCATTTGAAA 82 2045 1249095 N/A N/A 156157 156176 TCTTCTTTTTTCCTAAGTTA 65 2046 1249121 N/A N/A 161709 161728 TATGTATCCTTCTCTTTTTA 92 2047 1249147 N/A N/A 165658 165677 TAGAACAGTTCTAATTGTTA 95 2048 1249173 N/A N/A 170182 170201 AATGTGTAGCTCAATAACTT 47 2049 1249199 N/A N/A 171856 171875 TTCCCAATGTCTACTAGGAA 31 2050 1249225 N/A N/A 172637 172656 CAGCATCTATATACCTCTAA 23 2051 1249251 N/A N/A 174327 174346 GTCATGACTTTAAATACCAG 19 2052 1249277 N/A N/A 175566 175585 TTTCTTACCATTAATAACTC 40 2053 1249303 N/A N/A 176825 176844 CATGGCTATCATTTTAATAA 29 2054 1249329 N/A N/A 177648 177667 GATTGACCTATTACCAGTTA 45 2055 1249355 N/A N/A 178312 178331 TTACATATCTTATCAACACT 46 2056 1249381 N/A N/A 179609 179628 GTTTTTTCATCCATATGAAA 47 2057 1249407 N/A N/A 180430 180449 TAACATCATTCTAAAAGTTA 69 2058 1249433 N/A N/A 180935 180954 AAAATATTTATACTTACTCC 77 2059 1249459 N/A N/A 183649 183668 ATAATTTCCATTATATATAA 96 2060 1249485 N/A N/A 183975 183994 TTGCATCAACCAAATAGGGC 14 2061 1249511 N/A N/A 185231 185250 TGAGAATCTACACTTATCCT 59 2062 1249537 N/A N/A 185740 185759 TTTTTAAATTTTCCTAGGAT 80 2063 1249563 N/A N/A 187450 187469 TAACTGAATTCCTCTTCCCC 66 2064 1249589 N/A N/A 189973 189992 AGGCATTCTTCATAGGCAAC 24 2065 1249615 N/A N/A 191856 191875 TCCTTTCTCTCCTCTAACAA 65 2066 1249641 N/A N/A 200201 200220 GTGGTGTTCAAAATATACCT 52 2067 1249667 N/A N/A 200664 200683 CCTAAACATCATCATCCACA 47 2068 1249693 N/A N/A 202504 202523 AAGTTCTAAAATAAAATCAT 81 2069 1249719 N/A N/A 203014 203033 TTGCCACTAATTAATTCTAT 49 2070 1249745 N/A N/A 203760 203779 CTACATTTCTCATTTAACTA 57 2071 1249771 N/A N/A 205133 205152 ACCACTTTAAAATCTATCAC 48 2072 1249797 N/A N/A 207008 207027 TTTCAATTTCACATAGGTTA 51 2073 1249823 N/A N/A 208725 208744 CCTTTTTTTTCTTATTGCTA 42 2074 1249849 N/A N/A 210335 210354 ATTATATAAATATTTAGACT 80 2075 1249875 N/A N/A 213368 213387 AGTGACTTTTCCAAATATTA 42 2076 1249901 N/A N/A 215842 215861 ATTCCATAATTCTTTAGTTC 43 2077 1249927 N/A N/A 220875 220894 TCTTTCTTCCTACCAAGCTA 59 2078 1249953 N/A N/A 224198 224217 CAGCATGTTTATCTTAGTTC 17 2079 1249979 N/A N/A 228226 228245 TGTGATTCCTCATCAATACC 40 2080 1250005 N/A N/A 231098 231117 GCATGCACTTTTACTTTTCA 25 2081 1250031 N/A N/A 233414 233433 TAATGATCTAATAAACATCA 68 2082 1250057 N/A N/A 235526 235545 CTGTCTGTTTTCAATAGCCT 36 2083 1250083 N/A N/A 237406 237425 GTTAAATCAAATATCACCAA 42 2084 1250109 N/A N/A 240123 240142 ATTTACATTATTACCTGATA 70 2085 1250135 N/A N/A 243099 243118 TCAAAAAATTCTATTAAATT 85 2086 1250161 N/A N/A 246430 246449 GTGTAAGACACAAATTCTCC 23 2087 1250187 N/A N/A 249170 249189 CATATCTACTCACTTAGCTA 50 2088 1250213 N/A N/A 252473 252492 CTTCTCAAACATAAACTCCA 61 2089 1250239 4789 4808 254157 254176 TTGTGGTTTCTTTGAACCCA 26 2090 255550 255569 1250265 N/A N/A 255680 255699 ACAGTTTCACAAAATATCAA 58 2091 1250291 N/A N/A 258473 258492 GAAATATTCAATCTTTGCCC 65 2092 1250315 N/A N/A 260869 260888 ATCTCAAATCTTACCTCTTA 81 2093

TABLE 29 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SCN2A SEQ Compound 1 Start 1 Stop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA 17 227 1248350 250 269 168795 168814 CTGCTCCTTTAATCACTGTT 20 2094 1248376 624 643 170095 170114 GCTAATTTTCTAATAGGGTT 13 2095 1248402 1221 1240 183568 183587 TCAATATATTCATCCCAGTT 41 2096 1248428 2309 2328 199866 199885 GTCTCTTTCTTATTTCTGTT 32 2097 1248454 2507 2526 204409 204428 GTTTCACCTTTAACCATGGT 41 2098 1248480 3425 3444 227419 227438 GGTTGGAAATACAGCTGTCT 15 2099 1248506† 3896 3915 240314 240333 AGGTTTCGAACCAATTGTGC 24 2100 1248532 4461 4480 247895 247914 ACATTTTTCCACCTGGCAGT 24 2101 1248557 6049 6068 262577 262596 ACTTGATACCTTTTTAACTT 55 2102 1248583 6601 6620 263129 263148 ATGTTGAATTTACATAAAAA 77 2103 1248609 7212 7231 263740 263759 TATTTTTATTTTATGCCAAA 79 2104 1248634 7390 7409 263918 263937 GTAAAATTACTATTTACAAA 87 2105 1248660 7510 7529 264038 264057 ACCAATTACATCATATTACC 37 2106 1248685 7749 7768 264277 264296 GGCTTTTCATCATTGAGTGT 33 2107 1248710 7984 8003 264512 264531 ATCCTAGTCCTTGCTTCTTA 46 2108 1248735 8318 8337 264846 264865 TATAACTTCACTACCTGGTT 50 2109 1248761 8432 8451 264960 264979 ACAGCATTTTCCTGCATGCA 41 2110 1248787 8602 8621 265130 265149 TGTGTGTTCTTTACATTTGT 65 2111 1248811 8733 8752 265261 265280 TTGTAACTTTCCACTAGTCT 57 2112 1248837 N/A N/A 113946 113965 TGCTTTTCTTTAAATGATAA 73 2113 1248863 N/A N/A 117594 117613 TTATCACATTCCAATAAATA 85 2114 1248889 N/A N/A 123738 123757 CTACATTTTATCCTTTCCTA 74 2115 1248915 N/A N/A 126713 126732 TCAAACATCTATACTTGATC 72 2116 1248940 N/A N/A 128508 128527 TTAGGATATGGAGTTAAACC 89 2117 128551 128570 1248966 N/A N/A 140537 140556 CCTATATTTTCTTCTAGTAC 71 2118 1248992 N/A N/A 144250 144269 GGTCTTTGCTCATAATACCA 61 2119 1249018 N/A N/A 146235 146254 TCTAACTTATTCCTTAGTTA 87 2120 1249044 N/A N/A 147614 147633 GTACAATTTTTAAACTAGGC 70 2121 1249070 N/A N/A 152431 152450 GCTTTCATTTCCATCCTTTA 71 2122 1249096 N/A N/A 156175 156194 TTCCATTTCCTTCCTTTTTC 71 2123 1249122 N/A N/A 161817 161836 CAAGTCTATTTTCTTATCAA 75 2124 1249148 N/A N/A 165672 165691 GTATCAATTATAATTAGAAC 114 2125 1249174 N/A N/A 170184 170203 AAAATGTGTAGCTCAATAAC 54 2126 1249200 N/A N/A 171870 171889 ATTTAATGAATATTTTCCCA 45 2127 1249226 N/A N/A 172638 172657 ACAGCATCTATATACCTCTA 27 2128 1249252 N/A N/A 174390 174409 TAGTTCAGCATTACTAGTGT 19 2129 1249278 N/A N/A 175569 175588 TGGTTTCTTACCATTAATAA 16 2130 1249304 N/A N/A 176837 176856 TTTTCCTTATTTCATGGCTA 22 2131 1249330 N/A N/A 177671 177690 CCTCTCTTTTTCTTTAGTAC 22 2132 1249356 N/A N/A 178316 178335 GTACTTACATATCTTATCAA 30 2133 1249382 N/A N/A 179685 179704 TTTAGTCAAAACAATAATAA 94 2134 1249408 N/A N/A 180436 180455 GTATTATAACATCATTCTAA 25 2135 1249434 N/A N/A 181116 181135 TGCAGTAATTTACACAACTA 43 2136 1249460 N/A N/A 183650 183669 GATAATTTCCATTATATATA 74 2137 1249486 N/A N/A 183976 183995 GTTGCATCAACCAAATAGGG 19 2138 1249512 N/A N/A 185318 185337 TTCTCTATTTTACATTGAAC 46 2139 1249538 N/A N/A 185746 185765 ACTGTGTTTTTAAATTTTCC 35 2140 1249564 N/A N/A 187569 187588 AGAGAACAAATATTGAATAA 91 2141 1249590 N/A N/A 189974 189993 AAGGCATTCTTCATAGGCAA 26 2142 1249616 N/A N/A 191904 191923 TAGTTATTTTTTAAAGCCTT 52 2143 1249642 N/A N/A 200270 200289 GCATTTATCATTACACTCTT 24 2144 1249668 N/A N/A 200669 200688 TTATGCCTAAACATCATCAT 76 2145 1249694 N/A N/A 202506 202525 TTAAGTTCTAAAATAAAATC 78 2146 1249720 N/A N/A 203028 203047 CTACTAATCAACATTTGCCA 40 2147 1249746 N/A N/A 203763 203782 TCTCTACATTTCTCATTTAA 53 2148 1249772 N/A N/A 205201 205220 TAAGCATTTTATACTTGTAT 23 2149 1249798 N/A N/A 207009 207028 TTTTCAATTTCACATAGGTT 37 2150 1249824 N/A N/A 208813 208832 ATGTCTTCTTCCATTCTTTA 29 2151 1249850 N/A N/A 210346 210365 CTGATTCTCCCATTATATAA 51 2152 1249876 N/A N/A 213417 213436 ATGGAATCTCTCTCTACCTA 50 2153 1249902 N/A N/A 215847 215866 GAACAATTCCATAATTCTTT 35 2154 1249928 N/A N/A 220972 220991 ACTTCATATTTAAAGCATAA 49 2155 1249954 N/A N/A 224537 224556 GTCTTTTCTCCTAATTGTGA 38 2156 1249980 N/A N/A 228309 228328 ATTTTACATTCTATAATGTA 101 2157 1250006 N/A N/A 231374 231393 CCTATTCATTTACATTATTA 47 2158 1250032 N/A N/A 233663 233682 GCCTAGTTAAAATTTAACAA 68 2159 1250058 N/A N/A 235611 235630 ATATAGTTCAATACAAGGAA 80 2160 1250084 N/A N/A 237423 237442 CTTTTGTTTTCCTTTAGGTT 16 2161 1250110 N/A N/A 240470 240489 CATATTTCTTCTCATTCTTA 59 2162 1250136 N/A N/A 243102 243121 AAGTCAAAAAATTCTATTAA 83 2163 1250162 N/A N/A 246477 246496 CATCTGGTAAATATTATTTT 57 2164 1250188 N/A N/A 249349 249368 CATTTTTATTTTAATTGCTT 21 2165 1250214 N/A N/A 252565 252584 TGCATAATACATAAATGCAA 54 2166 1250240 N/A N/A 254182 254201 TTACAGCAGGTCGAGGTATG 60 2167 255575 255594 1250266 N/A N/A 255756 255775 GTCTGGACATTTCATAGGCT 20 2168 1250292 N/A N/A 258776 258795 TTTCTGACTTTATATTCTCT 59 2169 1250316 N/A N/A 260872 260891 CAGATCTCAAATCTTACCTC 55 2170

TABLE 30 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SCN2A SEQ Compound 1 Start 1 Stop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) control) NO  910064 7753 7772 264281 264300 GTCGGGCTTTTCATCATTGA 40  116  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA 37  227 1248351 264 283 168809 168828 GCCATCTTTTCATCCTGCTC 29 2171 1248377 625 644 170096 170115 AGCTAATTTTCTAATAGGGT 20 2172 1248403 1224 1243 183571 183590 TCCTCAATATATTCATCCCA 36 2173 1248429 2310 2329 199867 199886 CGTCTCTTTCTTATTTCTGT 18 2174 1248455 2510 2529 204412 204431 GGTGTTTCACCTTTAACCAT 82 2175 1248481 3427 3446 227421 227440 ATGGTTGGAAATACAGCTGT 28 2176 1248507 3958 3977 243130 243149 CTCAATGTATATATCTTCAA 35 2177 1248533 4463 4482 247897 247916 TCACATTTTTCCACCTGGCA 23 2178 1248558 6050 6069 262578 262597 TACTTGATACCTTTTTAACT 48 2179 1248584 6628 6647 263156 263175 GTGACAATTACTATTATCAA 45 2180 1248610 7213 7232 263741 263760 ATATTTTTATTTTATGCCAA 64 2181 1248635 7391 7410 263919 263938 GGTAAAATTACTATTTACAA 49 2182 1248661 7511 7530 264039 264058 AACCAATTACATCATATTAC 45 2183 1248711 7993 8012 264521 264540 CTACACTGCATCCTAGTCCT 58 2184 1248736 8322 8341 264850 264869 GTAATATAACTTCACTACCT 50 2185 1248762 8435 8454 264963 264982 GTAACAGCATTTTCCTGCAT 41 2186 1248788 8616 8635 265144 265163 ATTATAGTAATTAATGTGTG 68 2187 1248812 8737 8756 265265 265284 ATTTTTGTAACTTTCCACTA 93 2188 1248838 N/A N/A 113947 113966 TTGCTTTTCTTTAAATGATA 58 2189 1248864 N/A N/A 117621 117640 TTATAGTTTTTTACCCTCAA 60 2190 1248890 N/A N/A 123821 123840 TCAAATCATTCTACAATTCA 95 2191 1248916 N/A N/A 127155 127174 CATTTATTTATAAATTATAA 79 2192 1248941 N/A N/A 128512 128531 ATTGTTAGGATATGGAGTTA 62 2193 128555 128574 1248967 N/A N/A 140712 140731 GGAGTTTCTTACATATTTTA 84 2194 1248993 N/A N/A 144287 144306 AATTCTCTCCAAAATAATTA 74 2195 1249019 N/A N/A 146239 146258 ACCATCTAACTTATTCCTTA 58 2196 1249045 N/A N/A 148464 148483 TGGAGCTTATATTCTAGGTA 54 2197 1249071 N/A N/A 152539 152558 ATATTTTTAAAAACTTGGCT 74 2198 1249097 N/A N/A 156183 156202 TTAAATATTTCCATTTCCTT 95 2199 1249123 N/A N/A 161836 161855 CTTTCTTATTCCATAGGTTC 72 2200 1249149 N/A N/A 165819 165838 TTCATTATCCTTATTTGCAA 52 2201 1249175 N/A N/A 170220 170239 AAGAACACATAACATTGCCA 51 2202 1249201 N/A N/A 171878 171897 ACTTATTTATTTAATGAATA 74 2203 1249227 N/A N/A 172639 172658 TACAGCATCTATATACCTCT 31 2204 1249253 N/A N/A 174408 174427 CCATTTTCAAATGATAGGTA 40 2205 1249279 N/A N/A 175596 175615 GTCATTATCCACTAAGATAA 55 2206 1249305 N/A N/A 176843 176862 CAGGCATTTTCCTTATTTCA 19 2207 1249331 N/A N/A 177679 177698 AAATGTCACCTCTCTTTTTC 58 2208 1249357 N/A N/A 178317 178336 TGTACTTACATATCTTATCA 47 2209 1249383 N/A N/A 179765 179784 ATAATGAAATATCAACACTA 62 2210 1249409 N/A N/A 180452 180471 AAGTAATTAATTAAATGTAT 97 2211 1249435 N/A N/A 181315 181334 TTGTATTTCATAAAATATGC 44 2212 1249461 N/A N/A 183652 183671 GAGATAATTTCCATTATATA 50 2213 1249487 N/A N/A 183978 183997 ATGTTGCATCAACCAAATAG 40 2214 1249513 N/A N/A 185319 185338 ATTCTCTATTTTACATTGAA 45 2215 1249539 N/A N/A 185779 185798 TGGCTCTAAAATCTTGCTAA 26 2216 1249565 N/A N/A 187608 187627 ATGTAACCCACAAACTTGCA 46 2217 1249591 N/A N/A 189975 189994 AAAGGCATTCTTCATAGGCA 35 2218 1249617 N/A N/A 191905 191924 GTAGTTATTTTTTAAAGCCT 31 2219 1249643 N/A N/A 200273 200292 TAAGCATTTATCATTACACT 35 2220 1249669 N/A N/A 200681 200700 CATTCAACAACCTTATGCCT 50 2221 1249695 N/A N/A 202507 202526 TTTAAGTTCTAAAATAAAAT 65 2222 1249721 N/A N/A 203038 203057 AATGTTTCTTCTACTAATCA 36 2223 1249747 N/A N/A 203768 203787 CCATCTCTCTACATTTCTCA 46 2224 1249773 N/A N/A 205479 205498 ATACAGACAATTTATAGTAA 73 2225 1249799 N/A N/A 207015 207034 AGGAATTTTTCAATTTCACA 52 2226 1249825 N/A N/A 208862 208881 TCCTTTACATATATTAGATA 57 2227 1249851 N/A N/A 210347 210366 TCTGATTCTCCCATTATATA 51 2228 1249877 N/A N/A 213484 213503 CCAAAATTCATCTTACTGCT 37 2229 1249903 N/A N/A 215849 215868 ATGAACAATTCCATAATTCT 62 2230 1249929 N/A N/A 220980 220999 GTGTAATTACTTCATATTTA 31 2231 1249955 N/A N/A 224675 224694 TTATTTCTCACAACTCTATA 65 2232 1249981 N/A N/A 228316 228335 ATTCAGAATTTTACATTCTA 45 2233 1250007 N/A N/A 231422 231441 GCAGATAAATATTATACCCA 28 2234 1250033 N/A N/A 233733 233752 CACTTTTTAATTACCTGTAC 45 2235 1250059 N/A N/A 235626 235645 ATGGATAATACACCAATATA 36 2236 1250085 N/A N/A 237498 237517 CATTTGGAAACTACTTGTTA 70 2237 1250111 N/A N/A 241055 241074 TTGTACAAACTCATTCCTCC 34 2238 1250137 N/A N/A 243105 243124 TGTAAGTCAAAAAATTCTAT 75 2239 1250163 N/A N/A 246564 246583 AAGAAGTGAAAATCTAGCTA 67 2240 1250189 N/A N/A 249785 249804 TGGAAAGTTTTCATTTGCAA 38 2241 1250215 N/A N/A 253045 253064 TACATTTCTTTAGATAGGCA 29 2242 1250241 N/A N/A 254208 254227 TAACAGGCAATGAAAATATG 86 2243 255601 255620 1250267 N/A N/A 255841 255860 TCTATTCTAATTATTTTTCA 89 2244 1250293 N/A N/A 258834 258853 AACTAATAAATAAATACTTC 85 2245 1250317 N/A N/A 260876 260895 AGGTCAGATCTCAAATCTTA 55 2246

TABLE 31 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SCN2A SEQ Compound 1 Start 1 Stop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) control) NO  910069 7994 8013 264522 264541 CCTACACTGCATCCTAGTCC 55 39  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA 34 227 1248352 366 385 168911 168930 CTCTTAGCTTTCTCTTCTGC 22 2247 1248378 765 784 181676 181695 TCAAAAGTATAAATTCCTGT 42 2248 1248404 1225 1244 183572 183591 ATCCTCAATATATTCATCCC 14 2249 1248430 2312 2331 199869 199888 ACCGTCTCTTTCTTATTTCT 17 2250 1248456 2511 2530 204413 204432 AGGTGTTTCACCTTTAACCA 76 2251 1248482 3428 3447 227422 227441 TATGGTTGGAAATACAGCTG 16 2252 1248508 3975 3994 243147 243166 TTAATGGTTTTTCGCTGCTC 32 2253 1248534 4464 4483 247898 247917 TTCACATTTTTCCACCTGGC 8 2254 1248559 6061 6080 262589 262608 TTTCTTGTATATACTTGATA 47 2255 1248585 6629 6648 263157 263176 GGTGACAATTACTATTATCA 25 2256 1248611 7214 7233 263742 263761 GATATTTTTATTTTATGCCA 33 2257 1248636 7392 7411 263920 263939 GGGTAAAATTACTATTTACA 34 2258 1248662 7512 7531 264040 264059 GAACCAATTACATCATATTA 31 2259 1248686 7797 7816 264325 264344 ATATATTTTAAACAGATTTA 70 2260 1248737 8325 8344 264853 264872 CTGGTAATATAACTTCACTA 29 2261 1248763 8451 8470 264979 264998 TTTACCGTTCTTTATGGTAA 72 2262 1248789 8623 8642 265151 265170 AAGATGAATTATAGTAATTA 66 2263 1248813 8740 8759 265268 265287 TTAATTTTTGTAACTTTCCA 78 2264 1248839 N/A N/A 113966 113985 CCTTATCTCTCAATTACAAT 82 2265 1248865 N/A N/A 117677 117696 AAGATCATTTTATCCCCCTA 67 2266 1248891 N/A N/A 123949 123968 CTTATGGTCTTTAATAATAA 72 2267 1248917 N/A N/A 127158 127177 TCACATTTATTTATAAATTA 105 2268 1248942 N/A N/A 128514 128533 TAATTGTTAGGATATGGAGT 66 2269 128557 128576 1248968 N/A N/A 140789 140808 GAGAAATGTCCATTTAGGTC 61 2270 1248994 N/A N/A 144315 144334 AGCACAAGTCCAATTAGGCC 58 2271 1249020 N/A N/A 146246 146265 TTTAATCACCATCTAACTTA 79 2272 1249046 N/A N/A 148566 148585 GCTAATCATTTAACAAAAAT 86 2273 1249072 N/A N/A 152563 152582 ATTTTATATATAATTACTAA 66 2274 1249098 N/A N/A 156216 156235 GAACTTATCTTCCTTAGAAA 69 2275 1249124 N/A N/A 162088 162107 ACATAATTTTATATTAGTTT 113 2276 1249150 N/A N/A 165938 165957 GCTAGGCTTTCAATTAATAT 77 2277 1249176 N/A N/A 170274 170293 CCTGTGATCTCATTTTGCAA 44 2278 1249202 N/A N/A 171885 171904 ACTAGTCACTTATTTATTTA 39 2279 1249228 N/A N/A 172640 172659 CTACAGCATCTATATACCTC 34 2280 1249254 N/A N/A 174412 174431 CCTACCATTTTCAAATGATA 48 2281 1249280 N/A N/A 175597 175616 AGTCATTATCCACTAAGATA 42 2282 1249306 N/A N/A 176844 176863 ACAGGCATTTTCCTTATTTC 10 2283 1249332 N/A N/A 177749 177768 TACTGTAATTATTTTAGGTT 60 2284 1249358 N/A N/A 178320 178339 ATCTGTACTTACATATCTTA 33 2285 1249384 N/A N/A 179781 179800 ATCACATTACTTACACATAA 28 2286 1249410 N/A N/A 180456 180475 ATTCAAGTAATTAATTAAAT 77 2287 1249436 N/A N/A 181432 181451 ATTAATTAATTTAAAGGATC 92 2288 1249462 N/A N/A 183672 183691 ACTTGATTCACATCTAAATT 24 2289 1249488 N/A N/A 183997 184016 GCATATGTACTCAATACATA 34 2290 1249514 N/A N/A 185322 185341 TTTATTCTCTATTTTACATT 71 2291 1249540 N/A N/A 185780 185799 GTGGCTCTAAAATCTTGCTA 38 2292 1249566 N/A N/A 187837 187856 CTTTATTACATATTTAGGAA 82 2293 1249592 N/A N/A 189977 189996 TTAAAGGCATTCTTCATAGG 44 2294 1249618 N/A N/A 192377 192396 GTGATTCTATTCATTATTTA 34 2295 1249644 N/A N/A 200292 200311 CTTAGCATCATCATAAGTAT 29 2296 1249670 N/A N/A 200689 200708 ATTTAATCCATTCAACAACC 64 2297 1249696 N/A N/A 202508 202527 GTTTAAGTTCTAAAATAAAA 99 2298 1249722 N/A N/A 203161 203180 TCAGTCACTTTAATACTATT 25 2299 1249748 N/A N/A 203770 203789 TTCCATCTCTCTACATTTCT 26 2300 1249774 N/A N/A 205535 205554 TTCAGACCTTCCATTTCTCT 27 2301 1249800 N/A N/A 207030 207049 CGCTTGTTACTCCCTAGGAA 11 2302 1249826 N/A N/A 208866 208885 ATAATCCTTTACATATATTA 74 2303 1249852 N/A N/A 210369 210388 TCCATTCTTTCTATTTTCTC 18 2304 1249878 N/A N/A 213508 213527 CCAGGCATCTCAAATTCAAC 30 2305 1249904 N/A N/A 216015 216034 ACTTTCTTTAAAATTAACAA 90 2306 1249930 N/A N/A 221026 221045 AGTCATTTTTCTATTCCATT 11 2307 1249956 N/A N/A 224726 224745 CTCTTAGTAAATACCAGTTA 26 2308 1249982 N/A N/A 228460 228479 TTTAAATTCCTCTCTTTACC 74 2309 1250008 N/A N/A 231424 231443 AAGCAGATAAATATTATACC 47 2310 1250034 N/A N/A 233839 233858 GTGAAATACTACATTAGTAA 21 2311 1250060 N/A N/A 235627 235646 TATGGATAATACACCAATAT 26 2312 235682 235701 1250086 N/A N/A 237593 237612 TTCTAATTCCAAAAAGAGCA 46 2313 1250112 N/A N/A 241548 241567 TAGCGAATCAGTGTGAAGAA 34 2314 1250138 N/A N/A 243124 243143 GTATATATCTTCAAAGGCCT 16 2315 1250164 N/A N/A 246602 246621 CTTGATTCAAATCAGCAGCA 20 2316 1250190 N/A N/A 250030 250049 TACTGCATTTCCTTTTTTAA 28 2317 1250216 N/A N/A 253049 253068 ATAATACATTTCTTTAGATA 72 2318 1250242 N/A N/A 254373 254392 GTTATGCATTATATAATTTA 64 2319 1250268 N/A N/A 255845 255864 TTTCTCTATTCTAATTATTT 65 2320 1250294 N/A N/A 258972 258991 ACCAGGTTTTATAAACTCAC 36 2321 1250318 N/A N/A 261001 261020 ATAATCTGATTTAATCCTCA 72 2322

TABLE 32 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SCN2A ID Compound 1 Start 1 Stop 2 Start 2 Stop (% NO Number Site Site Site Site Sequence (5′ to 3′) control)  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA 15 227 1248353 369 388 168914 168933 GGTCTCTTAGCTTTCTCTTC 18 2323 1248379 784 803 181695 181714 AAGTATTTTAATAAGTGATT 82 2324 1248405 1227 1246 183574 183593 TTATCCTCAATATATTCATC 68 2325 1248431 2313 2332 199870 199889 GACCGTCTCTTTCTTATTTC 29 2326 1248457 2512 2531 204414 204433 AAGGTGTTTCACCTTTAACC 66 2327 1248483 3429 3448 227423 227442 GTATGGTTGGAAATACAGCT 33 2328 1248509 3985 4004 243157 243176 TAACATGGTCTTAATGGTTT 49 2329 1248535 4468 4487 247902 247921 TACTTTCACATTTTTCCACC 29 2330 1248560 6093 6112 262621 262640 ATGGGTGTTCCATCACATTC 38 2331 1248586 6630 6649 263158 263177 TGGTGACAATTACTATTATC 39 2332 1248612 7215 7234 263743 263762 GGATATTTTTATTTTATGCC 24 2333 1248637 7393 7412 263921 263940 TGGGTAAAATTACTATTTAC 55 2334 1248663 7515 7534 264043 264062 ATGGAACCAATTACATCATA 41 2335 1248687 7799 7818 264327 264346 CCATATATTTTAAACAGATT 63 2336 1248712 8000 8019 264528 264547 CAGAAACCTACACTGCATCC 62 2337 1248738 8327 8346 264855 264874 AACTGGTAATATAACTTCAC 40 2338 1248764 8484 8503 265012 265031 AACCTTTATTCTTTTGGCTT 52 2339 1248790 8648 8667 265176 265195 AACTTCCATTCCATGAAAAA 63 2340 1248814 8752 8771 265280 265299 GTCAATTTTTTATTAATTTT 82 2341 1248840 N/A N/A 113976 113995 GGGAAATCCACCTTATCTCT 62 2342 1248866 N/A N/A 117690 117709 GCAATTTCTTCCTAAGATCA 94 2343 1248892 N/A N/A 123960 123979 GTTGATTACTCCTTATGGTC 53 2344 1248918 N/A N/A 127253 127272 CAGTACTTAAAAATATATTA 90 2345 1248943 N/A N/A 128520 128539 TTTTAATAATTGTTAGGATA 57 2346 128563 128582 1248969 N/A N/A 140835 140854 TGGGAATTTTATCATACACT 66 2347 1248995 N/A N/A 144516 144535 GTCTACTTCCTATTTTCCAT 43 2348 1249021 N/A N/A 146247 146266 CTTTAATCACCATCTAACTT 82 2349 1249047 N/A N/A 148586 148605 CTTTCAGTATTTACAATCCA 69 2350 1249073 N/A N/A 152567 152586 ATCTATTTTATATATAATTA 86 2351 1249099 N/A N/A 156232 156251 GAACATTTCCAAAATTGAAC 87 2352 1249125 N/A N/A 162139 162158 TAGAAATAAATTTATACTAA 59 2353 1249151 N/A N/A 165997 166016 ATTTAAGTCACTAAAAAGCA 111 2354 1249177 N/A N/A 170466 170485 GAGTTTACTCCCTTACCTAA 41 2355 1249203 N/A N/A 171897 171916 AATCTCTGACTTACTAGTCA 39 2356 1249229 N/A N/A 172641 172660 ACTACAGCATCTATATACCT 44 2357 1249255 N/A N/A 174417 174436 ATTTTCCTACCATTTTCAAA 75 2358 1249281 N/A N/A 175601 175620 ATACAGTCATTATCCACTAA 53 2359 1249307 N/A N/A 176882 176901 TAATTATTTTCTAATTAGTC 79 2360 1249333 N/A N/A 177770 177789 GCATTATCCCCATTTGGATA 41 2361 1249359 N/A N/A 178353 178372 TCTGAATTCCACATACTTGA 46 2362 1249385 N/A N/A 179785 179804 AATGATCACATTACTTACAC 47 2363 1249411 N/A N/A 180476 180495 GGCAAAAATTCAACAAGACA 36 2364 1249437 N/A N/A 181443 181462 GCATTTTCCACATTAATTAA 30 2365 1249463 N/A N/A 183697 183716 AAATCATCTTAAATTAGTCT 87 2366 1249489 N/A N/A 184042 184061 ATTCTTATTTCATCTTGATA 54 2367 1249515 N/A N/A 185324 185343 GCTTTATTCTCTATTTTACA 25 2368 1249541 N/A N/A 185841 185860 GGTATTAGCTACTAATGTCC 41 2369 1249567 N/A N/A 187845 187864 ACTTTGACCTTTATTACATA 37 2370 1249593 N/A N/A 190062 190081 TCTATATTATAAAAAGGTAA 150 2371 1249619 N/A N/A 192381 192400 TTATGTGATTCTATTCATTA 99 2372 1249645 N/A N/A 200310 200329 TTAATATAATCCAAATGGCT 56 2373 1249671 N/A N/A 200697 200716 GAAGGCTTATTTAATCCATT 30 2374 1249697 N/A N/A 202643 202662 TGCCAGCTGTCATTTAGCAA 38 2375 1249723 N/A N/A 203163 203182 AGTCAGTCACTTTAATACTA 38 2376 1249749 N/A N/A 203773 203792 AAGTTCCATCTCTCTACATT 33 2377 1249775 N/A N/A 205663 205682 AAGAAATTCTTACATAGCTC 39 2378 1249801 N/A N/A 207058 207077 GTCTATTACTTCTTGAGTCA 33 2379 1249827 N/A N/A 208871 208890 TTATAATAATCCTTTACATA 69 2380 1249853 N/A N/A 210376 210395 GCTCTGTTCCATTCTTTCTA 38 2381 1249879 N/A N/A 213542 213561 GCCTATTCAATACCTACATT 72 2382 1249905 N/A N/A 216017 216036 ATACTTTCTTTAAAATTAAC 111 2383 1249931 N/A N/A 221909 221928 AGAGGATTTTCTCCTTGCCT 42 2384 1249957 N/A N/A 224770 224789 CAGATCATAATAACAATAAA 94 2385 1249983 N/A N/A 228556 228575 ATCTTTGTTTTTCCTTGTTA 27 2386 1250009 N/A N/A 231442 231461 GCCATTTTCCCTAAAATGAA 41 2387 1250035 N/A N/A 233992 234011 TTTAAGGTCATAATTACGAT 36 2388 1250061 N/A N/A 235628 235647 ATATGGATAATACACCAATA 47 2389 1250087 N/A N/A 237601 237620 CTATAATTTTCTAATTCCAA 62 2390 1250113 N/A N/A 241550 241569 AATAGCGAATCAGTGTGAAG 42 2391 1250139 N/A N/A 243457 243476 TATATGTATTTAAATTGGTA 94 2392 1250165 N/A N/A 246605 246624 AATCTTGATTCAAATCAGCA 30 2393 1250191 N/A N/A 250041 250060 ACAATATATTCTACTGCATT 48 2394 1250217 N/A N/A 253122 253141 TTAACTATATTAACATATAA 96 2395 1250243 N/A N/A 254524 254543 GAACATTTAATATTTTCACA 64 2396 1250269 N/A N/A 255848 255867 TTTTTTCTCTATTCTAATTA 104 2397 1250295 N/A N/A 259097 259116 ACAATGTTCTATTCTATTAA 64 2398 1250319 N/A N/A 261296 261315 TTTATATGTCCAAAATACTA 89 2399

TABLE 33 Reduction of SCN2A RNA by 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages at 4000 nM concentration in SH-SY5Y cells SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: SCN2A SEQ Compound 1 Start 1 Stop 2 Start 2 Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) control) NO  910263 N/A N/A 180777 180796 GCACTACCATGCCTTCACCA 29  227 1248354 371 390 168916 168935 TGGGTCTCTTAGCTTTCTCT 21 2400 1248380 786 805 181697 181716 GCAAGTATTTTAATAAGTGA 30 2401 1248406 1228 1247 183575 183594 TTTATCCTCAATATATTCAT 27 2402 1248432 2317 2336 199874 199893 ACTGGACCGTCTCTTTCTTA 38 2403 1248458 2513 2532 204415 204434 CAAGGTGTTTCACCTTTAAC 54 2404 1248484 3431 3450 227425 227444 TGGTATGGTTGGAAATACAG 24 2405 1248510 3994 4013 243166 243185 AGCATATTCTAACATGGTCT 15 2406 1248536 4503 4522 247937 247956 AGAGACAGATATCCAAGTCC 33 2407 1248561 6135 6154 262663 262682 GTTGAATTCTCATTCAGTTT 44 2408 1248587 6825 6844 263353 263372 AAATATATCCAGTTATACAA 53 2409 1248613 7216 7235 263744 263763 AGGATATTTTTATTTTATGC 29 2410 1248638 7394 7413 263922 263941 CTGGGTAAAATTACTATTTA 51 2411 1248664 7517 7536 264045 264064 TAATGGAACCAATTACATCA 37 2412 1248688 7800 7819 264328 264347 ACCATATATTTTAAACAGAT 51 2413 1248713 8002 8021 264530 264549 AGCAGAAACCTACACTGCAT 53 2414 1248739 8328 8347 264856 264875 TAACTGGTAATATAACTTCA 43 2415 1248765 8485 8504 265013 265032 AAACCTTTATTCTTTTGGCT 38 2416 1248791 8650 8669 265178 265197 TTAACTTCCATTCCATGAAA 64 2417 1248815 8754 8773 265282 265301 TAGTCAATTTTTTATTAATT 94 2418 1248841 N/A N/A 114398 114417 ACAATCTTTTCTATTAGGTA 52 2419 1248867 N/A N/A 117733 117752 AAACTATAAAAATAATCTAA 71 2420 1248893 N/A N/A 123985 124004 ATTATATTAAATCATATTTT 65 2421 1248919 N/A N/A 127286 127305 AATAAGATCCAAAATAGTAA 88 2422 1248944 N/A N/A 128521 128540 ATTTTAATAATTGTTAGGAT 108 2423 128564 128583 1248970 N/A N/A 141313 141332 ATTATCTTTTTTATATGCCC 61 2424 1248996 N/A N/A 144674 144693 TAGAAATATTCTACATCTTA 71 2425 1249022 N/A N/A 146255 146274 ATTCAACTCTTTAATCACCA 59 2426 1249048 N/A N/A 149090 149109 TCTTACTCTCCTACTTTCTA 62 2427 1249074 N/A N/A 152570 152589 TCCATCTATTTTATATATAA 64 2428 1249100 N/A N/A 156409 156428 CATCTCTCCTCATATTCATT 60 2429 1249126 N/A N/A 162345 162364 ATACTCTTTTCCTTTAGTTT 69 2430 1249152 N/A N/A 166019 166038 ACACCAATCTTATTTATCTC 54 2431 1249178 N/A N/A 170511 170530 TATTTATTTTCCAAATGTAA 43 2432 1249204 N/A N/A 171907 171926 CTGATTCTCTAATCTCTGAC 26 2433 1249230 N/A N/A 172642 172661 AACTACAGCATCTATATACC 43 2434 1249256 N/A N/A 174418 174437 CATTTTCCTACCATTTTCAA 66 2435 1249282 N/A N/A 175698 175717 GATACATCCCTTACCAGCCA 27 2436 1249308 N/A N/A 176888 176907 GAGAAATAATTATTTTCTAA 53 2437 1249334 N/A N/A 177771 177790 TGCATTATCCCCATTTGGAT 33 2438 1249360 N/A N/A 178407 178426 TAACCATTATATACCCACCA 48 2439 1249386 N/A N/A 179788 179807 ATAAATGATCACATTACTTA 55 2440 1249412 N/A N/A 180491 180510 ACATATGTAAACCCTGGCAA 50 2441 1249438 N/A N/A 181444 181463 TGCATTTTCCACATTAATTA 24 2442 1249464 N/A N/A 183698 183717 TAAATCATCTTAAATTAGTC 68 2443 1249490 N/A N/A 184276 184295 TTTATATTCACATACAAACA 78 2444 1249516 N/A N/A 185362 185381 CTTAAGAATTCTATTAAGCT 49 2445 1249542 N/A N/A 185943 185962 ATCAATTGATTTACTTATCA 83 2446 1249568 N/A N/A 188039 188058 GTCTGAATTATTAAATGTAA 54 2447 1249594 N/A N/A 190063 190082 GTCTATATTATAAAAAGGTA 32 2448 1249620 N/A N/A 192453 192472 AGCTAAAGAATTACTTTTTC 41 2449 1249646 N/A N/A 200315 200334 AGCAGTTAATATAATCCAAA 27 2450 1249672 N/A N/A 200750 200769 ATAATATTTATTAACTGTCT 43 2451 1249698 N/A N/A 202720 202739 TTACAGTAAATAACAAAAAA 91 2452 1249724 N/A N/A 203194 203213 TTCTTTTTAAATCCATGGCA 29 2453 1249750 N/A N/A 203776 203795 ACAAAGTTCCATCTCTCTAC 39 2454 1249776 N/A N/A 205718 205737 CTTTCTTGTTTCAATTGCCA 31 2455 1249802 N/A N/A 207283 207302 CTGGCATTAATATCAGGGTA 15 2456 1249828 N/A N/A 208931 208950 TATGTCTATTCAAATATTTT 65 2457 1249854 N/A N/A 210392 210411 GTTTCTTCAAATATTTGCTC 24 2458 1249880 N/A N/A 213546 213565 ACCTGCCTATTCAATACCTA 78 2459 1249906 N/A N/A 216211 216230 AGGTAAATCATCTATAGGAA 27 2460 1249932 N/A N/A 222126 222145 ATCAAATCTATAACATAATT 83 2461 1249958 N/A N/A 224957 224976 CTGTGACATTTATATAGCCT 28 2462 1249984 N/A N/A 229045 229064 TTAGTAATTTTATCAAATAA 65 2463 1250010 N/A N/A 231465 231484 GGTCAACTCCTAAATAAAGC 21 2464 1250036 N/A N/A 234115 234134 TTAAAATTACATTCTAGGCA 39 2465 1250062 N/A N/A 235629 235648 CATATGGATAATACACCAAT 48 2466 1250088 N/A N/A 237608 237627 ATATATTCTATAATTTTCTA 84 2467 1250114 N/A N/A 241552 241571 GCAATAGCGAATCAGTGTGA 23 2468 1250140 N/A N/A 243479 243498 ATTTGATTTTTATCTATGAA 69 2469 1250166 N/A N/A 246776 246795 CTTTTTAGCCATTTCAGCCT 42 2470 1250192 N/A N/A 250174 250193 TTATTCTTTTCTAAATGATT 53 2471 1250218 N/A N/A 253216 253235 GTCAAAACTTTTAAGATTTA 47 2472 1250244 N/A N/A 254626 254645 GCCTGTTTCATTAATGATTC 51 2473 1250270 N/A N/A 256686 256705 TGATAGCTCACAAATCCATC 50 2474 1250296 N/A N/A 259151 259170 CTTAATGCTACCTCATAGCA 53 2475 260853 260872 1250320 N/A N/A 261310 261329 AGTACAGAAATTAATTTATA 95 2476

Example 2: Effect of Modified Oligonucleotides on Human SCN2A RNA In Vitro, Multiple Doses

Modified oligonucleotides selected from Example 1 above were tested at various doses in SH-SY5Y cells. Cultured SH-SY5Y cells at a density of 20,000 cells perwell were treated using electroporation with various concentrations of modified oligonucleotide as specified in the tables below. After a treatment period of approximately 24 hours, total RNA was isolated from the cells and SCN2A RNA levels were measured by quantitative real-time RTPCR. Human SCN2A primer-probe set RTS36041 (described herein in Example 1) was used to measure RNA levels as described above. SCN2A RNA levels were normalized to total RNA content, as measured by RIBOGREEN®. 0.0 Reduction of SCN2A RNA is presented in the tables below as percent SCN2A RNA relative to the amount in untreated control cells (% control).

The half maximal inhibitory concentration (IC₅₀) of each modified oligonucleotide was calculated using a linear regression on a log/linear plot of the data in Excel.

TABLE 34 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 80.0 nM 400.0 nM 2000.0 nM 10000.0 nM (μM) 909951 126 64 30 8 0.79 909987 141 88 40 21 1.99 909981 136 84 50 14 1.95 909945 109 66 32 13 0.89 910381 145 86 46 15 1.91 910279 95 52 31 5 0.71 909958 92 61 34 20 1.00 909988 115 54 22 15 0.97 909946 99 66 46 11 1.23 910256 77 44 25 12 0.41 910023 97 73 47 38 2.63 910376 100 92 70 29 4.23 910269 54 40 34 30 0.10 910263 78 61 42 20 0.91 909947 68 54 27 14 0.41 910335 84 71 36 18 1.05 909989 91 70 39 41 1.11 910329 88 69 49 41 2.82 910342 78 58 39 15 0.75

TABLE 35 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 80.0 nM 400.0 nM 2000.0 nM 10000.0 nM (μM) 910342 91 60 19 22 0.54 910258 91 71 32 21 1.14 910330 95 90 57 22 2.51 910246 70 40 19 2 0.27 910366 95 66 32 10 0.93 910378 80 75 43 29 1.60 910355 71 58 22 7 0.43 909955 70 43 15 5 0.27 909985 83 46 23 26 0.42 909967 97 88 54 36 3.56 910265 83 55 22 19 0.63 910319 82 79 58 30 2.72 909980 102 64 43 23 1.47 910015 83 55 27 11 0.61 909950 84 63 31 12 0.76 909962 72 63 40 9 0.66 909956 88 81 46 26 1.85 910356 80 54 41 21 0.81 909951 74 52 38 12 0.54

TABLE 36 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 99 65 38 20 0.84 1248511 101 61 31 26 0.80 1249205 75 60 35 10 0.45 1248355 76 53 26 16 0.38 1248485 71 47 27 14 0.30 1249569 74 68 44 21 0.72 1249335 82 61 38 20 0.64 1249257 77 70 41 25 0.78 1250271 98 94 84 55 >5.0 1248512 100 83 35 18 0.95 1249258 84 60 38 14 0.59 1249284 77 55 33 15 0.45 1249336 71 57 27 20 0.39 1249726 80 60 32 23 0.57 1248356 82 58 33 17 0.53 1249232 69 55 32 17 0.37 1250246 91 68 40 17 0.78 1248486 111 67 51 29 1.35 1250064 100 68 36 23 0.89

TABLE 37 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 108 65 36 22 0.89 1249337 98 60 30 24 0.74 1248461 68 55 23 11 0.30 1248487 75 54 31 19 0.43 1249675 79 53 25 12 0.39 1248357 72 66 37 22 0.59 1249207 79 61 34 15 0.52 1250065 80 56 38 16 0.53 1250117 91 79 46 19 1.02 1249285 98 87 53 26 1.53 1249390 70 42 34 12 0.27 1249416 74 46 36 15 0.37 1248462 73 38 36 12 0.29 1249338 78 45 29 11 0.35 1249286 78 62 33 15 0.52 1249598 87 80 49 24 1.16 1249728 92 54 25 10 0.49 1249754 110 63 45 20 0.99 1248358 115 56 33 12 0.74

TABLE 38 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 128 79 33 22 1.13 1249417 65 41 15 9 0.18 1249313 76 38 24 7 0.27 1249729 73 47 18 9 0.28 1248385 75 61 30 12 0.44 1249495 92 60 33 16 0.62 1248489 80 62 28 8 0.46 1250119 101 81 47 23 1.23 1249599 87 81 43 18 0.95 1249755 100 76 48 20 1.12 1249677 91 72 40 21 0.88 1249963 90 80 38 24 1.00 1248359 79 52 33 18 0.46 1250015 92 87 52 48 3.22 1248718 89 71 41 34 1.16 1250146 77 50 28 20 0.40 1249418 76 45 25 12 0.32 1250198 115 76 42 24 1.19 1249444 141 77 36 13 1.08

TABLE 39 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 108 69 35 23 0.95 1249470 91 62 39 16 0.70 1248593 79 69 41 26 0.82 1249210 88 74 42 17 0.83 1249912 89 74 43 23 0.97 1248976 94 65 43 23 0.91 1249990 96 65 38 15 0.75 1249340 95 67 40 14 0.77 1248542 100 75 53 28 1.42 1249341 87 70 34 18 0.70 1249237 86 59 29 18 0.55 1249445 72 42 27 16 0.28 1248439 79 50 29 19 0.42 1249315 89 64 42 21 0.80 1250199 97 69 45 21 0.97 1250225 75 57 34 20 0.49 1249576 107 67 37 20 0.90 1249602 121 67 35 21 0.99 1250070 103 64 30 22 0.80

TABLE 40 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 102 61 33 22 0.80 1248466 105 53 32 10 0.62 1248414 88 69 32 9 0.60 1250148 89 60 34 11 0.57 1249316 82 67 35 15 0.61 1249160 83 66 35 15 0.61 909602 80 54 34 27 0.56 1248543 79 60 33 21 0.55 1248440 83 60 32 21 0.59 1250226 109 78 47 21 1.20 1249863 85 61 29 9 0.50 1249811 92 67 38 21 0.81 1249161 85 60 42 21 0.72 1250227 88 70 38 19 0.78 1248441 78 60 27 16 0.45 1250149 84 61 31 16 0.56 1248363 89 73 32 24 0.80 1249759 124 71 34 16 0.96 1249291 126 80 50 22 1.38

TABLE 41 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 91 57 27 12 0.53 1249187 102 78 49 19 1.15 1248519 91 73 44 20 0.94 1249448 91 71 37 30 0.99 1249266 80 56 28 13 0.44 1249344 87 58 27 24 0.59 1249370 79 67 40 24 0.75 1249890 80 69 36 21 0.69 1250021 84 48 25 10 0.39 1249371 91 77 59 20 1.27 1249527 89 82 47 17 1.02 1249163 102 90 61 28 1.89 1249995 85 61 31 18 0.58 1249267 86 59 36 21 0.65 1249164 43 32 13 7 <0.1 1248366 67 48 23 10 0.25 1249294 80 53 22 13 0.39 1249788 111 61 46 15 0.91 1249710 97 61 47 14 0.80

TABLE 42 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 85 58 26 19 0.52 1249216 99 78 43 13 0.93 1249528 95 89 56 22 1.45 1249632 80 82 39 18 0.85 1250204 77 70 39 18 0.67 1248522 110 71 43 14 0.95 1249554 87 71 41 24 0.91 1249580 73 61 40 20 0.55 1248368 81 61 23 10 0.44 1249296 88 47 21 9 0.39 1248394 89 72 33 13 0.68 1249842 97 85 48 23 1.28 1248524 79 55 36 25 0.57 1248446 90 60 30 24 0.67 1249452 100 60 29 26 0.78 1250050 87 54 34 20 0.58 1249920 81 54 24 19 0.44 1249712 140 72 37 18 1.12 1249868 92 58 32 17 0.62

TABLE 43 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 96 52 36 24 0.70 1249998 97 86 66 45 3.89 1248447 88 63 48 25 0.96 1249297 84 49 41 13 0.51 1249167 82 59 30 11 0.48 1248369 90 50 34 25 0.61 1249713 N.D. 54 33 10 1.98 1249401 67 57 37 27 0.47 1249349 91 83 57 35 2.02 1248395 97 66 36 25 0.87 1249427 86 67 51 24 1.01 1249869 111 103 61 36 2.63 1249685 72 51 33 17 0.38 1249711 97 64 51 27 1.15 1248445 77 62 41 31 0.81 1249633 71 50 35 16 0.36 1248523 95 71 40 21 0.91 1249893 137 83 50 37 1.93 1249659 90 56 33 13 0.57

TABLE 44 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 126 68 29 31 1.11 1249997 98 85 53 37 2.01 1249867 88 63 31 18 0.63 1249529 102 81 51 25 1.37 1249217 103 87 54 23 1.46 1249295 76 49 25 18 0.36 1249269 98 58 31 12 0.62 1248396 90 67 23 15 0.59 1249428 87 51 32 15 0.50 1249298 61 49 29 11 0.23 1249792 92 53 47 21 0.78 1249402 102 79 50 41 2.00 1248370 98 65 25 17 0.67 1248526 72 45 31 15 0.31 1249272 73 63 35 14 0.48 1250234 103 60 38 18 0.80 1249273 80 36 17 13 0.27 1250235 90 39 24 14 0.40 1248371 95 40 28 17 0.47

TABLE 45 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 127 79 30 16 1.01 1249403 85 47 30 17 0.45 1249377 76 60 37 16 0.51 1249169 89 63 32 20 0.66 1248475 96 76 44 19 1.01 1249429 105 80 54 30 1.60 1249222 81 42 22 10 0.32 1249274 76 50 26 13 0.35 1249170 77 51 31 9 0.38 1248476 81 67 36 15 0.62 1248398 91 58 33 22 0.66 1250236 94 77 44 22 1.04 1249196 113 83 41 25 1.27 1249482 87 51 43 23 0.66 1248372 64 54 30 17 0.30 1250184 69 72 24 21 0.49 1249483 76 52 24 23 0.39 1249639 107 60 34 11 0.71 1248425 85 56 32 17 0.53

TABLE 46 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 112 79 32 9 0.86 1250081 75 78 45 12 0.73 1249171 84 70 35 17 0.68 1249223 84 88 57 25 1.56 1249613 82 57 31 12 0.47 1248399 89 75 48 19 0.98 1249873 80 63 37 25 0.68 1249484 66 40 20 13 0.19 1249328 79 72 33 17 0.63 1250238 80 51 27 12 0.40 1249588 55 43 14 5 0.13 1249406 77 63 26 13 0.46 1249822 84 67 33 14 0.60 1249536 78 71 37 18 0.66 1248400 71 54 22 17 0.33 1249485 46 20 9 7 <0.1 1249953 73 39 12 8 0.21 1249251 106 69 29 13 0.76 1250161 100 62 27 13 0.65

TABLE 47 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 93 55 22 9 0.48 1249225 64 43 23 8 0.20 1248479 60 48 21 11 0.19 1249589 91 57 24 8 0.50 1250005 80 73 38 15 0.68 1250239 70 60 32 15 0.41 1248375 70 47 26 7 0.27 1248376 62 49 21 6 0.21 1248480 94 59 31 8 0.56 1250084 68 36 13 4 0.18 1249278 66 38 18 6 0.18 1249252 83 55 27 9 0.44 1249486 77 47 22 9 0.31 1248350 89 68 41 17 0.78 1250266 54 35 15 6 0.10 1250188 68 54 26 5 0.29 1249304 88 96 23 7 0.73 1249330 102 67 38 18 0.85 1249772 107 67 39 16 0.87

TABLE 48 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 83 53 31 19 0.49 1248532 93 94 56 23 1.59 1249642 108 62 31 17 0.76 1249408 91 68 31 15 0.66 1249590 106 72 30 22 0.90 1249226 110 63 36 14 0.80 1248429 77 58 26 21 0.46 1249305 55 41 18 10 0.12 1248377 96 71 35 16 0.79 1248533 98 64 42 14 0.79 1249539 75 66 48 19 0.72 1248481 77 58 26 15 0.42 1248534 91 64 34 15 0.66 1249306 83 59 23 11 0.45 1249930 82 48 28 11 0.39 1249800 62 27 16 8 0.11 1248404 106 86 47 23 1.31 1248482 122 44 29 9 0.65 1250138 105 63 28 27 0.84

TABLE 49 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 99 61 45 22 0.92 1248430 90 63 39 9 0.63 1249852 93 80 48 33 1.52 1250164 69 61 39 16 0.48 1250034 115 99 61 51 >5.0 1248352 96 79 54 39 2.09 1249462 88 86 50 43 2.48 1248585 75 55 40 29 0.60 1249722 115 86 57 23 1.57 1249956 72 97 58 31 2.17 1250060 76 82 63 30 1.90 1248353 82 62 39 29 0.81 1248612 95 76 55 38 1.96 1249515 94 69 48 24 1.06 1249983 70 65 52 31 1.04 1248431 85 77 51 20 1.04 1248535 103 88 73 47 >5.0 1249437 139 72 56 32 1.73 1249671 99 59 48 24 0.95

TABLE 50 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ ID 78.125 nM 313.5 nM 1250.0 nM 5000.0 nM (μM) 910263 98 55 30 16 0.62 1250165 103 76 63 30 1.81 1248483 70 48 31 14 0.32 1249801 90 73 33 21 0.79 1249749 61 71 58 27 1.05 1248510 55 33 25 7 0.10 1249802 56 35 21 8 0.11 1248354 74 53 21 15 0.34 1250010 89 64 45 27 0.96 1250114 92 86 48 16 1.07 1249438 79 67 28 18 0.56 1249854 97 62 41 46 1.56 1248484 57 39 22 9 0.13 1249204 66 47 22 12 0.24 1249282 74 52 28 15 0.36 1249906 75 73 52 21 0.93 1248406 97 91 53 26 1.56 1249646 145 88 48 39 2.02 910263 114 81 35 27 1.17

Example 3: Design of MOE Gapmer Modified Oligonucleotides Complementary to Human SCN2A Nucleic Acid

Modified oligonucleotides complementary to a human SCN2A nucleic acid were designed, as described in the tables below. “Start site” in the tables below indicates the 5′-most nucleoside to which the modified oligonucleotide is complementary in the target nucleic acid sequence. “Stop site” indicates the 3′-most nucleoside to which the modified oligonucleotide is complementary in the target nucleic acid sequence. Each modified oligonucleotide listed in the tables below is 100% complementary to SEQ ID NO: 1 (GENBANK Accession No. NM_001040142.2) or SEQ ID NO: 2 (GENBANK Accession No. NC_000002.12 truncated from nucleotides 165127001 to 165395000), or to both. ‘N/A’ indicates that the modified oligonucleotide is not 100% complementary to that particular target nucleic acid sequence.

The modified oligonucleotides in Table 51 are 5-10-5 MOE gapmers. The gapmers are 20 nucleosides in length, wherein the central gap segment consists of ten 2′-β-D-deoxynucleosides and the 5′ and 3′ wing segments each consists of five 2′-MOE nucleosides. The sugar motif for the gapmers is (from 5′ to 3′): eeeeeddddddddddeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. The gapmers have an internucleoside linkage motif of (from 5′ to 3′): soooossssssssssooss; wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage. Each cytosine residue is a 5-methyl cytosine.

TABLE 51 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages complementary to human SCN2A SEQ ID SEQ ID SEQ ID SEQ ID SEQ Compound NO: 1 NO: 1 NO: 2 NO: 2 ID ID SEQUENCE (5′ to 3′) Start Site Stop Site Start Site Stop Site NO. 1348240 GACCGAATTCTATTTTATAA N/A N/A 229460 229479 2477 1348241 ACCGAATTCTATTTTATAAA N/A N/A 229459 229478 2478 1348242 CCGAATTCTATTTTATAAAT N/A N/A 229458 229477 2479 1348243 CGAATTCTATTTTATAAATG N/A N/A 229457 229476 2480 1348244 GAATTCTATTTTATAAATGC N/A N/A 229456 229475 2481 1348245 AATTCTATTTTATAAATGCC N/A N/A 229455 229474 2482 1348248 ATGTAACCTTTATACATTTA N/A N/A 243913 243932 2483 1348250 ATTCTGCATGTAACCTTTAT N/A N/A 243920 243939 2484 1348251 TTCTGCATGTAACCTTTATA N/A N/A 243919 243938 2485 1348252 TGCATGTAACCTTTATACAT N/A N/A 243916 243935 2486 1348253 TCTGCATGTAACCTTTATAC N/A N/A 243918 243937 2487 1348254 CATGTAACCTTTATACATTT N/A N/A 243914 243933 2488 1348255 GCATGTAACCTTTATACATT N/A N/A 243915 243934 2489 1348256 TGTAACCTTTATACATTTAA N/A N/A 243912 243931 2490 1348257 GTAACCTTTATACATTTAAT N/A N/A 243911 243930 2491 1348258 CCAGTTTTTTCATTGCATCC N/A N/A 255533 255552 2492 1348259 GCATAATCCCATTATACAAA N/A N/A 244051 244070 2493 1348263 ATCATGCATAATCCCATTAT N/A N/A 244056 244075 2494 1348264 TCATGCATAATCCCATTATA N/A N/A 244055 244074 2495 1348265 CATAATCCCATTATACAAAT N/A N/A 244050 244069 2496 1348266 TGCATAATCCCATTATACAA N/A N/A 244052 244071 2497 1348267 CATGCATAATCCCATTATAC N/A N/A 244054 244073 2498 1348328 TCTTTCTTATTTCTGTTTCA 2306 2325 199863 199882 2499 1348343 CTCTTTCTTATTTCTGTTTC 2307 2326 199864 199883 2500 1348378 TGGACCGTCTCTTTCTTATT 2315 2334 199872 199891 2501 1348380 CTGGACCGTCTCTTTCTTAT 2316 2335 199873 199892 2502 1348396 CACGCTTACATCAAACATCT 4396 4415 247830 247849 2503 1348405 TATTTTTCTACACTGCTGCC 3513 3532 227507 227526 2504 1348411 ATATTTTTCTACACTGCTGC 3514 3533 227508 227527 2505 1348423 CATATTTTTCTACACTGCTG 3515 3534 227509 227528 2506 1348439 ATGTAATCACTTTCATCCAC 3537 3556 227531 227550 2507 1348440 AATCACTTTCATCCACGACA 3533 3552 227527 227546 2508 1348441 TAATCACTTTCATCCACGAC 3534 3553 227528 227547 2509 1348442 CCACGACATATTTTTCTACA 3521 3540 227515 227534 2510 1348443 ATCACTTTCATCCACGACAT 3532 3551 227526 227545 2511 1348444 ACGACATATTTTTCTACACT 3519 3538 227513 227532 2512 1348446 TCCACGACATATTTTTCTAC 3522 3541 227516 227535 2513 1348447 CACGACATATTTTTCTACAC 3520 3539 227514 227533 2514 1348448 GCATGTTTATCTTAGTTCTA N/A N/A 224196 224215 2515 1348449 CCATTTCTATAACTCAGCAA N/A N/A 180685 180704 2516 1348450 TTGACCACGCTTACATCAAA 4401 4420 247835 247854 2517 1348451 AGCATGTTTATCTTAGTTCT N/A N/A 224197 224216 2518 1348453 CATTTCTATAACTCAGCAAC N/A N/A 180684 180703 2519 1348455 ATTTCTATAACTCAGCAACC N/A N/A 180683 180702 2520 1348456 CATGTAATCACTTTCATCCA 3538 3557 227532 227551 2521

The modified oligonucleotides in Table 52 below are 6-10-4 MOE gapmers. The gapmers are 20 nucleosides in length, wherein the central gap segment consists of ten 2′-β-D-deoxynucleosides, the 5′ wing segment consists of six 2′-MOE nucleosides, and the 3′ wing segment consists of four 2′-MOE nucleosides. The sugar motif for the gapmers is (from 5′ to 3′): eeeeeeddddddddddeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. The gapmers have an internucleoside linkage motif of (from 5′ to 3′): sooooossssssssssoss; wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage. Each cytosine residue is a 5-methyl cytosine.

TABLE 52 6-10-4 MOE gapmers with mixed PO/PS internucleoside inkages complementary to human SCN2A SEQ ID SEQ ID SEQ ID SEQ ID SEQ Compound NO: 1 NO: 1 NO: 2 NO: 2 ID ID SEQUENCE (5′ to 3′) Start Site Stop Site Start Site Stop Site NO. 1348269 CACGCTTACATCAAACATCT 4396 4415 247830 247849 2503 1348270 TGACCACGCTTACATCAAAC 4400 4419 247834 247853 2522 1348271 GACCACGCTTACATCAAACA 4399 4418 247833 247852 29 1348275 ACCACGCTTACATCAAACAT 4398 4417 247832 247851 2025 1348277 CCACGCTTACATCAAACATC 4397 4416 247831 247850 419 1348279 GACCGTCTCTTTCTTATTTC 2313 2332 199870 199889 2326 1348282 CTCTTTCTTATTTCTGTTTC 2307 2326 199864 199883 2500 1348286 GTCTCTTTCTTATTTCTGTT 2309 2328 199866 199885 2097 1348289 CACGACATATTTTTCTACAC 3520 3539 227514 227533 2514 1348290 CCACGACATATTTTTCTACA 3521 3540 227515 227534 2510 1348291 ACGACATATTTTTCTACACT 3519 3538 227513 227532 2512 1348292 ACATATTTTTCTACACTGCT 3516 3535 227510 227529 643 1348295 ATATTTTTCTACACTGCTGC 3514 3533 227508 227527 2505 1348297 TGGACCGTCTCTTTCTTATT 2315 2334 199872 199891 2501 1348298 AATCACTTTCATCCACGACA 3533 3552 227527 227546 2508 1348299 CAGCATATTCTAACATGGTC 3995 4014 243167 243186 491 1348300 ATTTCTATAACTCAGCAACC N/A N/A 180683 180702 2520 1348302 ATGTAATCACTTTCATCCAC 3537 3556 227531 227550 2507 1348303 CATGTAATCACTTTCATCCA 3538 3557 227532 227551 2521 1348304 TCCACGACATATTTTTCTAC 3522 3541 227516 227535 2513 1348306 TAATCACTTTCATCCACGAC 3534 3553 227528 227547 2509 1348307 ATCACTTTCATCCACGACAT 3532 3551 227526 227545 2511 1348308 CCATTTCTATAACTCAGCAA N/A N/A 180685 180704 2516 1348309 TCAGCATGTTTATCTTAGTT N/A N/A 224199 224218 2523 1348310 CAGCATGTTTATCTTAGTTC N/A N/A 224198 224217 2079 1348311 AGCATGTTTATCTTAGTTCT N/A N/A 224197 224216 2518 1348312 GCATGTTTATCTTAGTTCTA N/A N/A 224196 224215 2515 1348313 TGCCATTTCTATAACTCAGC N/A N/A 180687 180706 2524 1348315 CATTTCTATAACTCAGCAAC N/A N/A 180684 180703 2519 1348316 TTTGCCATTTCTATAACTCA N/A N/A 180689 180708 909 1348319 GTAACCTTTATACATTTAAT N/A N/A 243911 243930 2491 1348320 GACCGAATTCTATTTTATAA N/A N/A 229460 229479 2477 1348321 CCGAATTCTATTTTATAAAT N/A N/A 229458 229477 2479 1348322 ACCGAATTCTATTTTATAAA N/A N/A 229459 229478 2478 1348323 GAATTCTATTTTATAAATGC N/A N/A 229456 229475 2481 1348324 CGAATTCTATTTTATAAATG N/A N/A 229457 229476 2480 1348325 AATTCTATTTTATAAATGCC N/A N/A 229455 229474 2482 1348326 TTCTATTTTATAAATGCCGA N/A N/A 229453 229472 854 1348327 ATTCTATTTTATAAATGCCG N/A N/A 229454 229473 931 1348329 GCATGTAACCTTTATACATT N/A N/A 243915 243934 2489 1348331 TCTGCATGTAACCTTTATAC N/A N/A 243918 243937 2487 1348332 TTCTGCATGTAACCTTTATA N/A N/A 243919 243938 2485 1348333 CTGCATGTAACCTTTATACA N/A N/A 243917 243936 1090 1348334 TGCATGTAACCTTTATACAT N/A N/A 243916 243935 2486 1348335 ATGTAACCTTTATACATTTA N/A N/A 243913 243932 2483 1348336 TGTAACCTTTATACATTTAA N/A N/A 243912 243931 2490 1348337 CATGTAACCTTTATACATTT N/A N/A 243914 243933 2488 1348338 TGCATAATCCCATTATACAA N/A N/A 244052 244071 2497 1348340 ATCATGCATAATCCCATTAT N/A N/A 244056 244075 2494 1348341 TCATGCATAATCCCATTATA N/A N/A 244055 244074 2495 1348342 CATGCATAATCCCATTATAC N/A N/A 244054 244073 2498 1348344 ATGCATAATCCCATTATACA N/A N/A 244053 244072 1166 1348345 CATAATCCCATTATACAAAT N/A N/A 244050 244069 2496 1348347 GCATAATCCCATTATACAAA N/A N/A 244051 244070 2493

The modified oligonucleotides in Table 53 below are 4-10-6 MOE gapmers. The gapmers are 20 nucleosides in length, wherein the central gap segment consists of ten 2′-β-D-deoxynucleosides, the 5′ wing segment consists of four 2′-MOE nucleosides, and the 3′ wing segment consists of six 2′-MOE nucleosides. The sugar motif for the gapmers is (from 5′ to 3′): eeeeddddddddddeeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. The gapmers have an internucleoside linkage motif of (from 5′ to 3′): sooossssssssssoooss; wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage. Each cytosine residue is a 5-methyl cytosine.

TABLE 53 4-10-6 MOE gapmers with mixed PO/PS internucleoside linkages complementary to human SCN2A SEQ SEQ SEQ SEQ ID ID ID ID NO: NO: NO: NO: 1 1 2 2 SEQ Compound SEQUENCE Start  Stop Start  Stop ID ID (5′ to 3′) Site Site Site Site NO. 1348348 CACGCTTACA 4396 4415 247830 247849 2503 TCAAACATCT 1348350 TTTGGGCCAT 411 430 168956 168975 2525 TTTCATCATC 1348353 GACCACGCTT 4399 4418 247833 247852 29 ACATCAAACA 1348355 CCACGCTTAC 4397 4416 247831 247850 419 ATCAAACATC 1348356 ACCACGCTTA 4398 4417 247832 247851 2025 CATCAAACAT 1348358 TCTCTTTCTT 2308 2327 199865 199884 2021 ATTTCTGTTT 1348360 GGACCGTCTC 2314 2333 199871 199890 2526 TTTCTTATTT 1348361 CTGGACCGTC 2316 2335 199873 199892 2502 TCTTTCTTAT 1348362 GACCGTCTCT 2313 2332 199870 199889 2326 TTCTTATTTC 1348364 CGTCTCTTTC 2310 2329 199867 199886 2174 TTATTTCTGT 1348365 CTCTTTCTTA 2307 2326 199864 199883 2500 TTTCTGTTTC 1348366 TCTTTCTTAT 2306 2325 199863 199882 2499 TTCTGTTTCA 1348367 GTCTCTTTCT 2309 2328 199866 199885 2097 TATTTCTGTT 1348369 CCACGACATA 3521 3540 227515 227534 2510 TTTTTCTACA 1348370 CACGACATAT 3520 3539 227514 227533 2514 TTTTCTACAC 1348371 ACGACATATT 3519 3538 227513 227532 2512 TTTCTACACT 1348373 GACATATTTT 3517 3536 227511 227530 720 TCTACACTGC 1348374 CATATTTTTC 3515 3534 227509 227528 2506 TACACTGCTG 1348375 TATTTTTCTA 3513 3532 227507 227526 2504 CACTGCTGCC 1348376 ACATATTTTT 3516 3535 227510 227529 643 CTACACTGCT 1348377 ATATTTTTCT 3514 3533 227508 227527 2505 ACACTGCTGC 1348379 GCATATTCTA 3993 4012 243165 243184 2527 ACATGGTCTT 1348381 TAATCACTTT 3534 3553 227528 227547 2509 CATCCACGAC 1348382 CATGTAATCA 3538 3557 227532 227551 2521 CTTTCATCCA 1348383 GTAATCACTT 3535 3554 227529 227548 796 TCATCCACGA 1348384 ATGTAATCAC 3537 3556 227531 227550 2507 TTTCATCCAC 1348385 ATCACTTTCA 3532 3551 227526 227545 2511 TCCACGACAT 1348386 AATCACTTTC 3533 3552 227527 227546 2508 ATCCACGACA 1348387 TCCACGACAT 3522 3541 227516 227535 2513 ATTTTTCTAC 1348388 CAGCATATTC 3995 4014 243167 243186 491 TAACATGGTC 1348392 CCATTTCTAT N/A N/A 180685 180704 2516 AACTCAGCAA 1348393 GCCATTTCTA N/A N/A 180686 180705 832 TAACTCAGCA 1348394 CATTTCTATA N/A N/A 180684 180703 2519 ACTCAGCAAC 1348395 ATTTCTATAA N/A N/A 180683 180702 2520 CTCAGCAACC 1348397 AGCATATTCT 3994 4013 243166 243185 2406 AACATGGTCT 1348399 CAGCATGTTT N/A N/A 224198 224217 2079 ATCTTAGTTC 1348403 TCAGCATGTT N/A N/A 224199 224218 2523 TATCTTAGTT 1348404 GCATGTTTAT N/A N/A 224196 224215 2515 CTTAGTTCTA 1348406 TATTTTATAA N/A N/A 229450 229469 2528 ATGCCGACTT 1348407 AGCATGTTTA N/A N/A 224197 224216 2518 TCTTAGTTCT 1348408 CCGAATTCTA N/A N/A 229458 229477 2479 TTTTATAAAT 1348410 ATTCTATTTT N/A N/A 229454 229473 931 ATAAATGCCG 1348412 GTAACCTTTA N/A N/A 243911 243930 2491 TACATTTAAT 1348413 GACCGAATTC N/A N/A 229460 229479 2477 TATTTTATAA 1348414 CGAATTCTAT N/A N/A 229457 229476 2480 TTTATAAATG 1348415 GAATTCTATT N/A N/A 229456 229475 2481 TTATAAATGC 1348416 AATTCTATTT N/A N/A 229455 229474 2482 TATAAATGCC 1348417 TTCTATTTTA N/A N/A 229453 229472 854 TAAATGCCGA 1348418 GCATGTAACC N/A N/A 243915 243934 2489 TTTATACATT 1348419 CATAATCCCA N/A N/A 244050 244069 2496 TTATACAAAT 1348420 TTCTGCATGT N/A N/A 243919 243938 2485 AACCTTTATA 1348421 TCTGCATGTA N/A N/A 243918 243937 2487 ACCTTTATAC 1348422 TGCATGTAAC N/A N/A 243916 243935 2486 CTTTATACAT 1348424 ATGTAACCTT N/A N/A 243913 243932 2483 TATACATTTA 1348425 CATGTAACCT N/A N/A 243914 243933 2488 TTATACATTT 1348426 TGTAACCTTT N/A N/A 243912 243931 2490 ATACATTTAA 1348427 CTGCATGTAA N/A N/A 243917 243936 1090 CCTTTATACA 1348428 GCATAATCCC N/A N/A 244051 244070 2493 ATTATACAAA 1348429 GTTTTTTCAT N/A N/A 255530 255549 2529 TGCATCCTCC 1348430 AGTTTTTTCA N/A N/A 255531 255550 2530 TTGCATCCTC 1348433 ATCATGCATA N/A N/A 244056 244075 2494 ATCCCATTAT 1348434 TCATGCATAA N/A N/A 244055 244074 2495 TCCCATTATA 1348435 TGCATAATCC N/A N/A 244052 244071 2497 CATTATACAA 1348436 ATGCATAATC N/A N/A 244053 244072 1166 CCATTATACA 1348437 CATGCATAAT N/A N/A 244054 244073 2498 CCCATTATAC 1348438 CCAGTTTTTT N/A N/A 255533 255552 2492 CATTGCATCC 1348445 CAGTTTTTTC N/A N/A 255532 255551 2531 ATTGCATCCT

The modified oligonucleotides in Table 54 below are 4-8-6 MOE gapmers. The gapmers are 18 nucleosides in length, wherein the central gap segment consists of eight 2′-β-D-deoxynucleosides, the 5′ wing segment consists of four 2′-MOE nucleosides, and the 3′ wing segment consists of six 2′-MOE nucleosides. The sugar motif for the gapmers is (from 5′ to 3′): eeeeddddddddeeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. The gapmers have an internucleoside linkage motif of (from 5′ to 3′): soosssssssssoooss; wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage. Each cytosine residue is a 5-methyl cytosine.

TABLE 54 4-8-6 MOE gapmers with mixed PO/PS internucleoside linkages complementary to human SCN2A SEQ SEQ SEQ SEQ ID ID ID ID NO: NO: NO: NO: 1 1 2 2 SEQ Compound SEQUENCE Start Stop Start Stop ID ID (5′ to 3′) Site Site Site Site NO. 1348917 CTATTTTAT N/A N/A 229453 229470 2532 AAATGCCGA 1348920 TCTGCATGT N/A N/A 243920 243937 2533 AACCTTTAT 1348922 CTGCATGTA N/A N/A 243919 243936 2534 ACCTTTATA 1348923 TGCATGTAA N/A N/A 243918 243935 2535 CCTTTATAC 1348924 TCTATTTTA N/A N/A 229454 229471 2536 TAAATGCCG 1348925 GCATGTAAC N/A N/A 243917 243934 2537 CTTTATACA 1348926 CATGTAACC N/A N/A 243916 243933 2538 TTTATACAT

The modified oligonucleotides in Table 55 below are 6-8-4 MOE gapmers. The gapmers are 18 nucleosides in length, wherein the central gap segment consists of eight 2′-β-D-deoxynucleosides, the 5′ wing segment consists of six 2′-MOE nucleosides, and the 3′ wing segment consists of four 2′-MOE nucleosides. The sugar motif for the gapmers is (from 5′ to 3′): eeeeeeddddddddeeee; wherein ‘d’ represents a 2′-N-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. The gapmers have an internucleoside linkage motif of (from 5′ to 3′): soooosssssssssoss; wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage. Each cytosine residue is a 5-methyl cytosine.

TABLE 55  6-8-4 MOE gapmers with mixed PO/PS internucleoside linkages complementary to human SCN2A SEQ SEQ SEQ SEQ ID ID ID ID NO: NO: NO: NO: 1 1 2 2 SEQ Compound SEQUENCE Start Stop Start Stop ID ID (5′ to 3′) Site Site Site Site NO. 1348918 CATGTAACC N/A N/A 243916 243933 2538 TTTATACAT 1348919 TCTATTTTA N/A N/A 229454 229471 2536 TAAATGCCG 1348927 GCATGTAAC N/A N/A 243917 243934 2537 CTTTATACA 1348931 CTGCATGTA N/A N/A 243919 243936 2534 ACCTTTATA 1348934 TCTGCATGT N/A N/A 243920 243937 2533 AACCTTTAT 1348935 TGCATGTAA N/A N/A 243918 243935 2535 CCTTTATAC 1348936 ACCCAGTTT 4776 4793 254144 254161 2539 TTTCATTGC

The modified oligonucleotides in Table 56 below are 5-8-5 MOE gapmers. The gapmers are 18 nucleosides in length, wherein the central gap segment consists of eight 2′-β-D-deoxynucleosides, the 5′ wing segment consists of five 2′-MOE nucleosides, and the 3′ wing segment consists of five 2′-MOE nucleosides. The sugar motif for the gapmers is (from 5′ to 3′): eeeeeddddddddeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. The gapmers have an internucleoside linkage motif of (from 5′ to 3′): sooosssssssssooss; wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage. Each cytosine residue is a 5-methyl cytosine.

TABLE 56  5-8-5 MOE gapmers with mixed PO/PS internucleoside linkages complementary to human SCN2A SEQ SEQ SEQ SEQ ID ID ID ID NO: NO: NO: NO: SEQ Compound SEQUENCE Start Stop Start Stop ID ID (5′ to 3′) Site Site Site Site NO. 1348928 GCATGTAAC N/A N/A 243917 243934 2537 CTTTATACA 1348929 TGCATGTAA N/A N/A 243918 243935 2535 CCTTTATAC 1348930 CATGTAACC N/A N/A 243916 243933 2538 TTTATACAT 1348932 TCTATTTTA N/A N/A 229454 229471 2536 TAAATGCCG 1348933 CTATTTTAT N/A N/A 229453 229470 2532 AAATGCCGA 1348937 CTGCATGTA N/A N/A 243919 243936 2534 ACCTTTATA 1348938 TCTGCATGT N/A N/A 243920 243937 2533 AACCTTTAT 1348939 ACCCAGTTT 4776 4793 254144 254161 2539 TTTCATTGC 255537 255554

Example 4: Tolerability of Modified Oligonucleotides Complementary to Human SCN2A in Wild-Type Mice, 3 Hour Study

Modified oligonucleotides described above were tested in wild-type female C57/B16 mice to assess the tolerability of the oligonucleotides. Additionally, Comparator Compound No. 1506060 was tested. Wild-type female C57/B16 mice each received a single ICV dose of 700 μg of modified oligonucleotide as listed in the tables below. Each treatment group consisted of 3 mice. A group of 4 mice received PBS as a negative control for each experiment (identified in separate tables below). At 3 hours post-injection, mice were evaluated according to seven different criteria. The criteria are (1) the mouse was bright, alert, and responsive; (2) the mouse was standing or hunched without stimuli; (3) the mouse showed any movement without stimuli; (4) the mouse demonstrated forward movement after it was lifted; (5) the mouse demonstrated any movement after it was lifted; (6) the mouse responded to tail pinching; (7) regular breathing. For each of the 7 criteria, a mouse was given a subscore of 0 if it met the criteria and 1 if it did not (the functional observational battery score or FOB). After all 7 criteria were evaluated, the scores were summed for each mouse and averaged within each treatment group.

TABLE 57 Tolerability scores in mice at 700 μg dose Compound ID 3 hr. FOB PBS 0.00 1248353 4.00 1248354 1.33 1248355 2.67 1248356 3.33 1248357 2.33 1248358 2.67 1248366 0.00 1248368 1.00 1248369 1.33 1248396 0.00 1248398 1.67 1248400 4.00 1248414 0.67 1248425 0.33 1248430 7.00 1248439 1.00 1248440 0.67 1248441 1.33 1248461 2.00 1248462 1.33 1248466 1.00 1248476 1.00 1248481 1.00 1248487 0.00

TABLE 58 Tolerability scores in mice at 700 μg dose Compound ID 3 hr. FOB PBS 0.00 1248429 1.00 1249990 1.00 1250148 0.00 1250225 0.00

TABLE 59 Tolerability scores in mice at 700 μg dose Compound ID 3 hr. FOB PBS 0.00 910009 0.00 1248427 0.00 1248428 1.00 1248431 0.00 1248488 1.67 1248531 0.33 1249989 0.00 1348240 1.00 1348241 1.67 1348242 0.67 1348243 1.67 1348244 1.00 1348245 0.00 1348248 0.00 1348250 3.00 1348251 1.00 1348252 1.00 1348253 0.00 1348254 0.00 1348255 0.00 1348256 0.00 1348257 0.33 1348258 1.33 1348259 1.00 1348263 0.00 1348264 0.00 1348265 0.00 1348266 0.00 1348267 0.00 1348269 0.00 1348270 1.00 1348271 0.00 1348275 0.00 1348277 0.00 1348279 0.00

TABLE 60 Tolerability scores in mice at 700 μg dose Compound ID 3 hr. FOB PBS 0.00 1348282 1.00 1348286 1.00 1348289 1.00 1348290 0.00 1348291 0.00 1348292 0.00 1348295 2.00 1348297 0.00 1348298 0.00 1348299 0.00 1348300 1.00 1348302 0.00 1348303 0.00 1348304 0.00 1348306 0.00 1348307 0.00 1348308 0.00 1348309 0.00 1348310 0.00 1348311 1.00 1348312 1.67 1348313 0.00 1348316 0.00 1348319 0.00 1348320 0.00 1348321 0.00 1348322 1.67 1348323 1.00 1348324 2.33 1348325 0.33 1348326 3.00 1348327 2.00 1348376 0.33 1348377 1.00 1348378 1.00 1348379 1.67 1348380 1.00 1348381 0.00 1348382 0.00 1348383 2.00 1348384 0.33 1348385 1.00 1348386 0.33 1348387 0.00 1348388 0.00

TABLE 61 Tolerability scores in mice at 700 μg dose Compound ID 3 hr. FOB PBS 0.00 1348328 1.67 1348329 0.00 1348331 0.00 1348332 0.00 1348333 0.00 1348334 0.00 1348335 0.00 1348336 0.00 1348337 0.00 1348338 0.00 1348340 0.00 1348341 0.00 1348342 0.00 1348343 0.00 1348344 0.00 1348345 0.00 1348347 0.00 1348348 0.00 1348350 0.00 1348353 4.00 1348355 0.00 1348356 0.00 1348358 0.00 1348360 1.00 1348361 1.00 1348362 0.00

TABLE 62 Tolerability scores in mice at 700 μg dose Compound ID 3 hr. FOB PBS 0.00 1348364 1.00 1348365 0.00 1348366 0.00 1348367 0.00 1348369 1.00 1348370 0.00 1348371 0.00 1348373 1.00 1348374 2.00 1348375 0.00 1348392 0.00 1348393 0.00 1348394 0.00 1348395 0.00 1348396 0.00 1348397 0.00 1348399 0.00 1348424 0.00 1348425 0.00 1348426 0.00 1348427 0.00 1348428 0.00 1348429 1.00 1348430 3.00 1348433 1.00 1348434 0.00 1348435 0.00 1348436 0.00 1348437 0.00 1348438 0.00 1348448 1.00 1348449 0.00 1348450 2.00 1348451 0.00 1348453 0.00 1348455 0.00 1348456 0.00 1348917 0.00 1348918 0.00 1348919 1.00 1348920 2.00 1348922 1.00 1348923 0.00

TABLE 63 Tolerability scores in mice at 700 μg dose Compound ID 3 hr. FOB PBS 0.00 1348315 0.00 1348403 2.33 1348404 0.00 1348405 2.67 1348406 2.67 1348407 0.00 1348408 0.00 1348410 2.67 1348411 1.00 1348412 0.00 1348413 0.00 1348414 1.00 1348415 0.67 1348416 0.00 1348417 1.00 1348418 0.00 1348419 0.00 1348420 1.00 1348421 1.00 1348422 0.00 1348423 2.00 1348439 0.00 1348440 0.00 1348441 0.00 1348442 0.00 1348443 1.00 1348444 0.00 1348445 2.00 1348446 1.33 1348924 1.00 1348925 0.00 1348926 0.00 1348927 0.33 1348928 0.00 1348929 0.00 1348930 0.00 1348931 0.00 1348932 1.33 1348933 0.00 1348934 0.33 1348935 0.00 1348936 2.00 1348937 1.00 1348938 1.00 1348939 1.33

TABLE 64 Tolerability scores in mice at 700 μg dose Compound ID 3 hr. FOB PBS 0.00 1348447 0.00

TABLE 65 Tolerability scores in mice at 700 μg dose Compound ID 3 hr. FOB PBS 0.00 1348259 0.00 1348289 0.00 1348290 0.00 1348331 0.00 1348347 0.00 1348937 0.00

TABLE 66 Tolerability scores in mice at 700 μg dose Compound No. 3 hr. FOB PBS 0.00 1506060 6.00

Example 5: Tolerability of Modified Oligonucleotides Complementary to Human SCN2A in Rats, 3 mg Dose

Modified oligonucleotides described above were tested in rats to assess the tolerability of the oligonucleotides. Sprague Dawley rats each received a single intrathecal (IT) dose of 3 mg of modified oligonucleotide listed in the tables below. Each treatment group consisted of 3-4 rats. A group of 4 rats received PBS as a negative control for each experiment (identified in separate tables below). At 3 hours post-injection, movement in 7 different parts of the body were evaluated for each rat. The 7 body parts are (1) the rat's tail; (2) the rat's posterior posture; (3) the rat's hind limbs; (4) the rat's hind paws; (5) the rat's forepaws; (6) the rat's anterior posture; (7) the rat's head. For each of the 7 different body parts, each rat was given a sub-score of 0 if the body part was moving or 1 if the body part was paralyzed (the functional observational battery score or FOB). After each of the 7 body parts were evaluated, the sub-scores were summed for each rat and then averaged for each group. For example, if a rat's tail, head, and all other evaluated body parts were moving 3 hours after the 3 mg IT dose, it would get a summed score of 0. If another rat was not moving its tail 3 hours after the 3 mg IT dose but all other evaluated body parts were moving, it would receive a score of 1. The scores were averaged for each treatment group, and presented in the tables below. Values marked with the symbol “‡” indicate groups that had 3 or fewer animals in the group.

TABLE 67 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.00 1248429 2.00 1248487 0.25 1249990 2.00‡ 1250148 0.00‡ 1250225 0.25

TABLE 68 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.00 910009 1.00 1248427 0.00 1248428 1.00 1248431 0.67 1248488 1.33 1248531 0.33 1249989 1.33 1348240 0.33 1348241 0.00 1348242 0.00 1348243 3.00 1348244 1.67 1348245 0.67 1348248 0.33 1348250 3.00 1348251 2.33 1348252 0.33 1348253 1.67 1348254 0.00 1348255 0.33 1348256 1.00 1348257 0.33 1348258 1.00 1348259 0.67 1348263 0.00

TABLE 69 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.00 1348264 0.00 1348265 0.33 1348266 0.00 1348267 0.00 1348269 0.00 1348270 2.67 1348271 2.00 1348275 0.00 1348277 0.33 1348279 0.00 1348282 2.33 1348286 2.33 1348289 0.00 1348290 0.00 1348291 0.00 1348292 0.00 1348295 2.33

TABLE 70 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.00 1348297 0.33 1348298 1.33 1348299 1.33 1348300 2.33 1348302 0.00 1348303 0.00 1348304 0.33

TABLE 71 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.00 1348306 0.67 1348307 3.00 1348308 0.00 1348309 1.00 1348310 0.67 1348311 2.00 1348312 2.00 1348313 2.00

TABLE 72 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.00 1348316 0.33 1348319 1.67 1348320 0.33 1348321 0.00 1348322 0.00‡ 1348323 1.33 1348324 2.00 1348325 0.33 1348326 2.67 1348327 3.00 1348376 0.67 1348377 0.67 1348378 0.67 1348379 1.33 1348380 0.67 1348381 0.67 1348382 0.67 1348383 2.00 1348384 0.00 1348385 0.00 1348386 0.00 1348387 0.00 1348388 0.33

TABLE 73 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.00 1348328 2.33 1348329 0.33 1348331 0.33 1348332 0.67 1348333 0.33 1348334 0.00 1348335 0.33 1348336 0.33 1348337 0.00 1348338 1.00 1348340 0.00 1348341 0.00 1348342 0.00 1348343 1.33 1348344 1.00 1348345 1.33 1348347 0.33

TABLE 74 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.25 1348348 0.67 1348350 1.33 1348353 1.67 1348355 0.00 1348356 0.00 1348358 0.00 1348360 2.00 1348361 2.67 1348362 2.00 1348364 2.67 1348365 1.33 1348366 1.00 1348367 1.67 1348369 0.33 1348370 0.33 1348371 0.67 1348373 3.00 1348374 3.33 1348375 0.67 1348392 0.33

TABLE 75 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.00 1348393 1.33 1348394 0.67 1348395 0.00 1348396 0.00 1348397 1.33 1348399 0.00 1348424 2.33 1348425 0.00 1348426 0.00 1348427 2.00 1348428 0.00 1348429 1.67 1348430 3.00 1348433 0.00 1348434 0.00 1348435 0.00 1348436 0.00 1348437 0.00 1348438 0.33 1348448 2.00 1348449 0.00 1348450 2.67

TABLE 76 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.25 1348451 3.00 1348453 1.33 1348455 1.33 1348456 0.00 1348917 1.00 1348918 0.00 1348919 2.00 1348920 3.00 1348922 2.67 1348923 1.67 1348924 3.00 1348925 3.00 1348926 0.00 1348927 0.33 1348928 0.33 1348929 0.00 1348930 0.00 1348931 0.00 1348932 2.00 1348933 2.00 1348934 1.00 1348935 0.00 1348936 2.00 1348937 0.67 1348938 2.00 1348939 2.00

TABLE 77 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.25 1348315 1.67 1348403 2.00 1348404 1.00 1348405 2.33 1348406 4.00 1348407 0.33 1348408 0.00 1348410 2.00 1348411 2.00 1348412 0.00 1348413 0.67

TABLE 78 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.00 1348414 3.00 1348415 2.00 1348416 0.67 1348417 0.67 1348418 0.00 1348419 0.00 1348420 2.00 1348421 2.00 1348422 1.33 1348423 3.00

TABLE 79 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.00 1348439 2.67 1348440 0.33 1348441 1.00 1348442 0.00 1348443 1.00

TABLE 80 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.00 1348444 0.00 1348445 3.00 1348446 0.00 1348447 0.67

TABLE 81 Tolerability scores in rats at 3 mg dose Compound ID 3 hr. FOB PBS 0.25 1348259 0.75 1348289 0.50 1348290 0.75 1348331 1.00 1348347 0.50 1348937 1.25

Example 6: Effect of Modified Oligonucleotides on Human SCN2A RNA In Vitro, Multiple Doses

Modified oligonucleotides selected from the examples above were tested at various doses in SH-SY5Y cells. Cultured SH-SY5Y cells at a density of 20,000 cells per well were treated using electroporation with various concentrations of modified oligonucleotide as specified in the tables below. After a treatment period of approximately 24 hours, total RNA was isolated from the cells and SCN2A RNA levels were measured by quantitative real-time RTPCR. Human SCN2A primer-probe set RTS36041 (described herein above) was used to measure RNA levels. SCN2A RNA levels were normalized to total RNA content, as measured by GAPDH. Levels of GAPDH were measured using human primer probe set RTS104 (forward sequence GAAGGTGAAGGTCGGAGTC, designated herein as SEQ ID NO: 7; reverse sequence GAAGATGGTGATGGGATTTC, designated herein as SEQ ID NO: 8; probe sequence CAAGCTTCCCGTTCTCAGCC, designated herein as SEQ ID NO: 9). Reduction of SCN2A RNA is presented in the tables below as percent SCN2A RNA relative to the amount in untreated control cells (% control). The results for each separate experiment are presented in separate tables below.

The half maximal inhibitory concentration (IC₅₀) of each modified oligonucleotide was calculated using a linear regression on a log/linear plot of the data in Excel.

TABLE 82 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ No. 39 nM 156 nM 625 nM 2500 nM 10000 nM (μM) 910009 81 62 49 25 12 0.5 1248427 73 74 49 31 23 0.6 1348253 59 42 27 15 5 0.1 1348259 89 66 33 22 11 0.4 1348290 60 51 30 17 17 0.1 1348291 96 71 34 24 6 0.5 1348316 78 61 33 11 7 0.3 1348320 90 64 53 25 18 0.6 1348343 94 80 58 33 13 0.9 1348371 90 70 62 34 13 0.8 1348411 118 92 95 73 17 3.9 1348435 82 116 76 34 11 1.5 1348444 111 77 48 19 3 0.7 1348935 67 60 47 35 17 0.4

TABLE 83 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ No. 39 nM 156 nM 625 nM 2500 nM 10000 nM (μM) 1248487 133 168 103 63 10 3.8 1348266 106 100 85 40 21 2.1 1348292 101 96 69 33 21 1.5 1348328 72 72 63 30 12 0.6 1348345 110 112 77 43 19 2.1 1348347 94 73 43 17 12 0.5 1348373 94 82 36 13 9 0.5 1348374 106 92 63 37 23 1.5 1348417 106 92 45 32 12 0.9 1348420 111 106 122 120 138 >10.0 1348436 128 120 81 45 13 2.2 1348438 95 90 84 46 36 3.5 1348447 169 123 98 41 13 2.4 1348936 126 148 92 83 29 7.2

TABLE 84 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ No. 39 nM 156 nM 625 nM 2500 nM 10000 nM (μM) 1248488 133 118 57 26 11 1.4 1249990 103 102 52 35 19 1.3 1348271 84 106 71 36 13 1.4 1348275 106 111 109 93 110 >10.0 1348302 99 89 48 17 7 0.7 1348331 111 97 62 21 9 1.0 1348360 98 97 80 28 10 1.3 1348376 86 80 69 39 10 1.0 1348421 97 91 66 34 19 1.3 1348439 93 71 42 21 19 0.6 1348449 111 91 61 24 13 1.1 1348456 100 83 60 31 22 1.1 1348937 81 88 65 33 12 0.9 1348938 93 65 56 37 26 1.0

TABLE 85 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ No. 39 nM 156 nM 625 nM 2500 nM 10000 nM (μM) 1250148 93 73 56 20 8 0.6 1348277 80 70 59 27 13 0.6 1348303 109 80 34 12 23 0.7 1348304 85 74 54 28 11 0.6 1348332 95 56 58 23 28 0.7 1348333 75 81 48 30 14 0.6 1348365 96 80 72 37 14 1.2 1348366 136 84 72 39 89 >10.0 1348383 77 75 42 21 14 0.4 1348384 100 76 60 44 19 1.3 1348422 94 82 72 25 11 0.9 1348440 104 80 19 15 13 0.5 1348923 107 89 84 46 16 2.0 1348939 96 85 60 37 15 1.1

TABLE 86 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ No. 39 nM 156 nM 625 nM 2500 nM 10000 nM (μM) 1250225 91 119 56 32 13 1.2 1348251 91 91 88 55 24 3.2 1348282 117 90 52 38 15 1.2 1348289 81 64 39 25 12 0.4 1348306 79 75 51 22 13 0.5 1348338 89 72 35 13 16 0.4 1348369 107 121 124 97 139 >10.0 1348385 108 92 75 61 27 3.1 1348423 107 101 86 44 13 2.0 1348427 87 68 67 42 21 1.1 1348441 98 81 60 38 21 1.2 1348442 114 87 95 33 25 2.2 1348928 129 93 110 90 130 >10.0 1348931 91 91 78 54 39 4.6

TABLE 87 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ No. 39 nM 156 nM 625 nM 2500 nM 10000 nM (μM) 1348307 82 76 67 37 14 1.0 1348342 87 71 60 25 13 0.7 1348386 98 91 65 37 15 1.2 1348433 90 75 68 55 24 2.0 1348435 94 84 60 36 23 1.2 1348443 81 74 52 32 17 0.7 1348934 81 66 55 32 15 0.6

Example 7: Effect of Modified Oligonucleotides on Human SCN2A RNA In Vitro, Multiple Doses

Modified oligonucleotides selected from the examples above were tested at various doses in SH-SY5Y cells. Cultured SH-SY5Y cells at a density of 35,000 cells per well were treated using electroporation with various concentrations of modified oligonucleotide as specified in the tables below. After a treatment period of approximately 24 hours, total RNA was isolated from the cells and SCN2A RNA levels were measured by quantitative real-time RTPCR. Human SCN2A primer-probe set RTS36041 (described herein above) was used to measure RNA levels. SCN2A RNA levels were normalized to total RNA content, as measured by GAPDH. Levels of GAPDH were measured using human primer probe set RTS104 (forward sequence GAAGGTGAAGGTCGGAGTC, designated herein as SEQ ID NO: 7; reverse sequence GAAGATGGTGATGGGATTTC, designated herein as SEQ ID NO: 8; probe sequence CAAGCTTCCCGTTCTCAGCC, designated herein as SEQ ID NO: 9). Reduction of SCN2A RNA is presented in the tables below as percent SCN2A RNA relative to the amount in untreated control cells (% control).

The half maximal inhibitory concentration (IC₅₀) of each modified oligonucleotide was calculated in Graphpad Prism using log(inhibitor) vs. normalized response—Variable slope curve fitting.

TABLE 88 Dose-dependent reduction of human SCN2A RNA in SH-SY5Y cells by modified oligonucleotides Compound SCN2A RNA (% control) IC₅₀ No. 0.005 nM 0.013 nM 0.032 nM 0.08 nM 0.2 nM 0.5 nM 1.28 nM 3.2 nM 8.0 nM 20.0 nM (μM) 1348259 94 95 90 86 62 40 29 21 6 6 0.4 1348289 91 83 85 74 58 48 26 14 7 6 0.3 1348290 100 85 86 85 76 48 35 21 10 8 0.6 1348331 87 100 93 82 67 48 32 22 7 11 0.5 1348347 84 85 90 80 62 40 22 12 7 5 0.3 1348937 94 95 92 92 78 58 48 25 16 13 1.0

Example 8: Effect of Modified Oligonucleotides on Human SCN2A in Transgenic Mice

Modified oligonucleotides described above were tested in a human SCN2A transgenic mouse model. Transgenic mice that express a human SCN2A transcript were generated in a C57Bl/6 background. Transgenic mice may be prepared and are available from commercial and academic research facilities; for examples of transgenic mice that express human neurological genes see, for example, Heintz et al., 2002, Nature reviews Neuroscience 2, 861-870.

Treatment

Human SCN2A transgenic mice were divided into groups of 2 mice each. Each mouse received a single ICV bolus of 350 μg of modified oligonucleotide. A group of 4 mice received PBS as a negative control.

RNA Analysis

Two weeks post treatment, mice were sacrificed, and RNA was extracted from cortical brain tissue and spinal cord for quantitative real-time RTPCR analysis to measure the amount of SCN2A RNA using Human primer probe set RTS36041 (described in Example 1 above). Results are presented as percent human SCN2A RNA relative to the amount in PBS treated animals, normalized to mouse GAPDH RNA (% control). Mouse GAPDH RNA was amplified using primer probe set mGapdh_LTS00102 (forward sequence GGCAAATTCAACGGCACAGT, designated herein as SEQ ID NO: 13; reverse sequence GGGTCTCGCTCCTGGAAGAT, designated herein as SEQ ID NO: 14; probe sequence AAGGCCGAGAATGGGAAGCTTGTCATC, designated herein as SEQ ID NO: 15).

As shown in the tables below, treatment with modified oligonucleotides resulted in reduction of SCN2A RNA in comparison to the PBS control.

TABLE 89 Reduction of human SCN2A RNA in transgenic mice SCN2A RNA (% control) Compound ID CORTEX SPINAL CORD PBS 100  100  1248353 58 65 1248354 62 69 1248357 76 84 1248358 65 74 1248368 109  83 1248369 113  91 1248396 57 70 1248398 102  77 1248400 59 63 1248414 73 66 1248425 83 71 1248441 77 72 1248461 87 73 1248462 84  73‡ 1248466 58 50 1248476 45 42 1248481 71 66 1248487 24 35 1248489 36 29 1248510 48 44 1248526 68 62 1248543 111  81 1248585 73 60 1248593 37 64 1249160 62 82 1249161 48 78 1249164 46 59 1249169 49 73 1249170 53 80 1249204 50 81 1249205 43 76 1249210 52 76 1249222 46 61 1249225 44 60 1249237 43 48 1249252 80 87 1249266 76 85 1249269 58 70 1249272 74 71 1249273 89 90 1249274 83 84 1249282 53 63 1249284 69 80 1249286 46 62 1249295 97 100  1249296 121  87 1249297 103  91 1249298 65 76 1249313  84‡  76‡ 1249315 57 75 1249316 57 86 ‡indicates groups with only 1 PCR value

TABLE 90 Reduction of human SCN2A RNA in transgenic mice SCN2A RNA (% control) Compound ID CORTEX SPINAL CORD PBS 100  100  1249328 43 58 1249337 54 53 1249338 36 51 1249340 35 51 1249341 37 50 1249377 63 66 1249390 33 46 1249401 43 58 1249403 63 75 1249406 55 65 1249416 44 63 1249417 30 46 1249418 35 47 1249428 54 54 1249445 54 64 1249482 81 72 1249483 89 70 1249484 65 60 1249485 55 56 1249486 71 80 1249495 62 67 1249536 73 83 1249588 45 58 1249599 50 64 1249613 57 61 1249633 80 88 1249639 79 69 1249675 54 53 1249677 112  81 1249685 68 67 1249726 42 42 1249728 66 60 1249729 66 54 1249800 54 45 1249822 65 75 1249867 70 72 1249873 85 69 1249953 28 39 1249990 22 46 1250021 86 69 1250065 54 34 1250070  89‡  63‡ 1250148 13 25 1250149 26 36 1250161 62 66 1250164 60 64 1250184 55 53 1250225 16 23 1250235 49 60 1250238 73 93 1250239 65 70 1250266 53 64 909945 40 58 909947 40 48 909950 62 65 909951 62 68 909955 58 52 909962 66 75 909985 46 55 910015 38 47 910246 57 67 910263 38 51 910265 54 62 910269 35 52 910279 48 47 910342 42 44 910355 72 76 910356 69 80 910366 51 52 1248363 25 71 1248429  9 21 1248511 34 30 1249576 60 66 1249589 58 51 1249811 47 63 1250227 37 46 1250246 37 59 909533 59 57 909603 55 54 909995 36 40 910010 41 29 910061 78 77 910249 58 68 910250 81 74 910267 81 76 910307 72 69 910314  46‡ 57 910315 68 73 910341 61 55 910372 70 59 1248423 63 63 1248444 62 69 1248474 83 81 1248490 84 82 1248672 59 82 1248717 45 57 1248728 61 70 1249320 53 65 1249346 63 66 1249361 76 65 1249501 116‡ 40 1249533 78 65 1249687 38 45 1249789 71 70 1249967 55 60 1250101 53 52 1248355 41 60 1248356 43 67 1248366 43 39 1248430 31 28 1248439 39 42 1248440 36 43 ‡indicates groups with only 1 PCR value

TABLE 91 Reduction of human SCN2A RNA in transgenic mice SCN2A RNA (% control) Compound ID CORTEX SPINAL CORD PBS 100 100 910009 26 38 1248427 22 47 1248488 26 18 1248531 43 43 1249989 40 55 1348240 50 56 1348241 75 83 1348242 83 99 1348243 107 109 1348244 98 101 1348245 82 93 1348248 40 60 1348250 37 45 1348251 25 41 1348252 39 49 1348253 18 32 1348254 55 74 1348255 59 75 1348256 45 55 1348257 48 67 1348258 59 59 1348259 11 22 1348263 47 55 1348264 49 67 1348265 38 43 1348266 24 37 1348267 45 49 1348269 49 47 1348270 35 38 1348271 15 36 1348275 24 30 1348277 22 43 1348279 21 37 1348282 16 30 1348286 23 46 1348289 7 18 1348290 7 18 1348291 8 17 1348292 14 32 1348295 35 65 1348297 20 34 1348298 40 32 1348299 38 32 1348300 89 77 1348302 8 16 1348303 23 22 1348304 12 24 1348306 21 37 1348307 22 37 1348308 44 49 1348309 18 33 1348310 34 46 1348311 65 70 1348312 29 46 1348313 31 48 1348316 30 48 1348319 48 60 1348320 19 35 1348321 76 100 1348322 69 72 1348323 84 96 1348324 96 108 1348325 76 85 1348326 34 47 1348327 46 56 1348376 21 33 1348377 31 35 1348378 40 45 1348379 31 33 1348380 23 29 1348381 42 33 1348382 39 37 1348383 14 26 1348384 21 53 1348385 14 15 1348386 24 34 1348387 41 38 1348388 40 49 1348328 21 33 1348329 66 76

TABLE 92 Reduction of human SCN2A RNA in transgenic mice SCN2A RNA (% control) Compound ID CORTEX SPINAL CORD PBS 100 100 1348331 12 21 1348332 14 27 1348333 15 21 1348334 49 53 1348335 35 42 1348336 50 46 1348337 43 51 1348338 17 23 1348340 50 48 1348341 49 48 1348342 21 22 1348343 27 37 1348344 39 37 1348345 29 32 1348347 11 20 1348348 33 32 1348350 54 86 1348353 36 39 1348355 52 51 1348356 46 53 1348358 25 42 1348360 27 40 1348361 23 46 1348362 33 37 1348364 16 33 1348365 17 35 1348366 26 45 1348367 16 35 1348369 15 36 1348370 29 39 1348371 26 33 1348373 15 20 1348374 20 37 1348375 49 49 1348392 62 56 1348393 33 43 1348394 60 73 1348395 57 69 1348396 37 47 1348397 41 43

TABLE 93 Reduction of human SCN2A RNA in transgenic mice SCN2A RNA (% control) Compound ID CORTEX SPINAL CORD PBS 100 100 1348399 86 63 1348424 76 67 1348425 90 89 1348426 72 64 1348427 36 38 1348428 63 46 1348429 68 73 1348430 76 79 1348433 49 60 1348434 66 68 1348435 50 47 1348436 60 60 1348437 78 72 1348438 50 52 1348448 67 73 1348449 50 53 1348450 54 46 1348451 54 64 1348453 75 74 1348455 75 69 1348456 42 38 1348917 60 61 1348918 83 81 1348919 74 70 1348920 47 55 1348922 34 31 1348923 29 36 1348924 45 51 1348925 57 53 1348926 86 78 1348927 46 48 1348928 30 38 1348929 48 54 1348930 85 92 1348931 20 35 1348932 56 48 1348933 71 78 1348934 12 23 1348935 42 40 1348936 28 35 1348937 11 26 1348938 29 37 1348939 20 25 1348315 59 72 1348403 88 96 1348404 50 57 1348405 55 70 1348406 71 70 1348407 50 53 1348408 91 111 1348410 38 54 1348411 27 42 1348412 56 62 1348413 56 70 1348414 91 98 1348415 93 104 1348416 95 107 1348417 30 52 1348418 67 77 1348419 47 49 1348420 38 49 1348421 26 33 1348422 38 48 1348423 22 37 1348439 12 16 1348440 12 25 1348441 36 54 1348442 8 20 1348443 21 32 1348444 10 26 1348445 53 80 1348446 17 39 1348447 14 27

Example 9: Potency of Modified Oligonucleotides Complementary to Human SCN2A RNA in Transgenic Mice

Modified oligonucleotides described above were tested in human SCN2A transgenic mice (described herein above).

Treatment

Human SCN2A transgenic mice were divided into groups of 4 mice each. Each mouse received a single ICV bolus of modified oligonucleotide at the doses indicated in tables below. A group of 8 mice received PBS as a negative control.

RNA Analysis

Two weeks post treatment, mice were sacrificed, and RNA was extracted from the cortex and spinal cord for quantitative real-time RTPCR analysis of RNA expression of SCN2A using primer probe set RTS36041 (described herein in Example 1). Results are presented as percent human SCN2A RNA relative to the amount in PBS treated animals, normalized to mouse GAPDH RNA. Mouse GAPDH was amplified using primer probe set mGapdh_LTS00102 (described herein above). The half maximal effective dose (ED₅₀) of each modified oligonucleotide was calculated using GraphPad Prism 7 software (GraphPad Software, San Diego, CA). ED₅₀ values were calculated from dose and individual animal SCN2A RNA levels using custom equation Motulsky: Agonist vs response—Variable slope (four parameters) Y=Bottom+(Top−Bottom)/(1+(10{circumflex over ( )}log EC50/X){circumflex over ( )}HillSlope), with the following constraints: bottom>lowest value in data set in order to compare across ASOs (4.5 and 9.4 for cortex and spinal cord, respectively), top=100, HillSlope<−1 and >−2.

As shown in the table below, treatment with modified oligonucleotides resulted in dose-responsive reduction of SCN2A RNA in comparison to the PBS control.

TABLE 94 Reduction of human SCN2A RNA in transgenic mice SCN2A RNA (% control) ED₅₀ (μg) Compound Dose SPINAL SPINAL ID (μg) CORTEX CORD CORTEX CORD PBS N/A 100 100 N/A N/A 1348259 3 96 83 86 26 10 94 84 30 82 47 100 49 27 300 17 17 700 8 16 1348271 3 115 95 191 93 10 99 90 30 98 75 100 72 51 300 36 36 700 21 25 1348289 3 106 86 57 21 10 98 71 30 77 44 100 31 32 300 7 13 700 5 11 1348290 3 99 93 63 29 10 81 72 30 76 52 100 44 33 300 10 25 700 9 14 1348331 3 106 95 36 28 10 73 78 30 55 50 100 34 27 300 11 21 700 7 16 1348347 3 90 94 88 40 10 100 92 30 84 60 100 49 31 300 14 19 700 9 17 1348383 3 118 103 186 49 10 109 81 30 84 63 100 70 39 300 41 23 700 18 20 1348385 3 121 93 123 86 10 95 75 30 86 73 100 62 34 300 21 20 700 13 14 1348439 3 103 110 137 70 10 97 106 30 96 70 100 70 41 300 19 25 700 11 20 1348440 3 124 104 158 60 10 105 73 30 109 95 100 77 38 300 18 20 700 13 16 1348934 3 116 108 56 33 10 95 92 30 72 56 100 31 30 300 10 22 700 12 19 1348937 3 125 94 73 34 10 109 81 30 73 57 100 41 43 300 15 28 700 9 18 

1. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to an equal length portion of an SCN2A nucleic acid, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
 2. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 16-2531, wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
 3. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or 18 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 2532-2539, wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
 4. The oligomeric compound of any of claims 1 to 3, wherein the modified oligonucleotide is at least 90% complementary to an equal length portion of SEQ ID NO: 2 and is not more than 50% complementary to an equal length portion of SEQ ID NO:
 1. 5. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein a) the nucleobase sequence of the modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases complementary to an equal length portion of nucleobases 199863-199905, 227493-22755, 243124-243204, 247823-247921, 254142-254177, 168911-168945, 170026-170061, 183519-183562, 188630-188668, 199912-199962, 227419-227450, or 238173-238192 of SEQ ID NO: 2, provided that the modified oligonucleotide does not comprise more than six LNA nucleosides; or b) the nucleobase sequence of the modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases complementary to an equal length portion of nucleobases 243917-244073, 170174-170200, 176724-176751, 180772-180801, 183968-184016, 202877-202906, 224198-224217, 224199-224218, or 243918-243937 of SEQ ID NO: 2, wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
 6. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein a) the nucleobase sequence of the modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases of a sequence selected from SEQ ID NOs: 336, 488, 2021, 2097, 2174, 2250, 2326, 2403, 2499, 2500, 2501, 2502, 2526; 181, 259, 643, 720, 796, 2504, 2505, 2506, 2507, 2508, 2509, 2510, 2511, 2512, 2513, 2514, 2521; 491, 567, 644, 721, 797, 2177, 2253, 2315, 2329, 2406, 2527; 29, 30, 107, 108, 185, 186, 263, 264, 341, 342, 419, 420, 1796, 1871, 1948, 2025, 2101, 2178, 2254, 2330, 2503, 2517, 2522; 1016, 1093, 1104, 1169, 1246, 1323, 1400, 1477, 1554, 1708, 1785, 1860, 1937, 2014, 1631, 2090, 2539; 18, 96, 485, 561, 638, 715, 791, 868, 2247, 2323, 2400; 174, 1328, 1405, 1482, 1559, 1636, 1713, 1790, 1865, 1942, 2019; 20, 98, 253, 332, 410, 1406, 1483, 1560, 1637, 1714, 1791, 1866, 1943; 21, 411, 1407, 1484, 1561, 1638, 1715; 24, 414, 871, 948, 1025, 1100; 25, 337, 415, 490, 566, 2099, 2176, 2252, 2328, 2405; and 182; provided that the modified oligonucleotide does not comprise more than six LNA nucleosides; or b) wherein the nucleobase sequence of the modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases of a sequence selected from SEQ ID NOs: 1090, 1166, 2484, 2485, 2487, 2493, 2496, 2497, 2498, 2533, 2534, 2535, 2537; 302, 1513, 1667, 1744, 1819, 1896, 1973; 148, 226, 1364, 1441, 1518, 1595, 1672, 1749; 227, 1292, 1369, 1446, 1523, 1600, 1677, 1754, 1829; 228, 1679, 1756, 1831, 1908, 1985, 2061, 2138, 2214, 2290; 1226, 1303, 1380, 1457, 1534, 1611; 2079; 2523; and 2477 wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
 7. The oligomeric compound of any of claims 1-6, comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of any of SEQ ID NOs: 2487, 2493, 2510, or
 2514. 8. The oligomeric compound of any of claims 1-6, comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or 18 contiguous nucleobases of SEQ ID NO:
 2534. 9. The oligomeric compound of any of claims 1-8, wherein the modified oligonucleotide has a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the nucleobase sequence of SEQ ID NO: 1 or SEQ ID NO: 2 when measured across the entire nucleobase sequence of the modified oligonucleotide.
 10. The oligomeric compound of claim 9 wherein the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to an intronic region of the nucleobase sequence of SEQ ID NO: 2; an untranslated region of the nucleobase sequence of SEQ ID NO: 2; or an intron/exon junction region of the nucleobase sequence of SEQ ID NO:
 2. 11. The oligomeric compound of any of claims 1-10, wherein the nucleobase sequence of the modified oligonucleotide is no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, or no more than 95% complementary to an exonic region of the nucleobase sequence of SEQ ID NO:
 2. 12. The oligomeric compound of any of claims 1-11, wherein the modified oligonucleotide consists of 10 to 25, 10 to 30, 10 to 50, 12 to 20, 12 to 25, 12 to 30, 12 to 50, 13 to 20, 13 to 25, 13 to 30, 13 to 50, 14 to 20, 14 to 25, 14 to 30, 14 to 50, 15 to 20, 15 to 25, 15 to 30, 15 to 50, 16 to 18, 16 to 20, 16 to 25, 16 to 30, 16 to 50, 17 to 20, 17 to 25, 17 to 30, 17 to 50, 18 to 20, 18 to 25, 18 to 30, 18 to 50, 19 to 20, 19 to 25, 19 to 30, 19 to 50, 20 to 25, 20 to 30, 20 to 50, 21 to 25, 21 to 30, 21 to 50, 22 to 25, 22 to 30, 22 to 50, 23 to 25, 23 to 30, or 23 to 50 linked nucleosides.
 13. The oligomeric compound of any of claims 1-11, wherein the modified oligonucleotide consists of 17-19 or 21-30 linked nucleosides.
 14. The oligomeric compound of any of claims 1-13, wherein the modified oligonucleotide consists of 16, 17, 18, 19, or 20 linked nucleosides.
 15. The oligomeric compound of claim 14, wherein the modified oligonucleotide consists of 20 linked nucleosides.
 16. The oligomeric compound of claim 14, wherein the modified oligonucleotide consists of 18 linked nucleosides.
 17. The oligomeric compound of any of claims 1-16, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified sugar moiety.
 18. The oligomeric compound of claim 17, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety.
 19. The oligomeric compound of claim 18, wherein the bicyclic sugar moiety comprises a 4′-2′ bridge, wherein the 4′-2′ bridge is selected from —CH₂—O—; and —CH(CH₃)—O—.
 20. The oligomeric compound of any of claims 17-19, wherein the modified oligonucleotide does not comprise more than six bicyclic sugar moieties.
 21. The oligomeric compound of claim 17, wherein the modified oligonucleotide does not comprise a bicyclic sugar moiety.
 22. The oligomeric compound of any of claims 17-20, wherein the modified oligonucleotide does not comprise more than six LNA sugar moieties.
 23. The oligomeric compound of any of claims 17-21, wherein the modified oligonucleotide does not comprise a LNA sugar moiety.
 24. The oligomeric compound of any of claims 17-23, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic modified sugar moiety.
 25. The oligomeric compound of claim 24, wherein the non-bicyclic modified sugar moiety is a 2′-MOE sugar moiety or a 2′-OMe sugar moiety.
 26. The oligomeric compound of any of claims 17-25, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a sugar surrogate.
 27. The oligomeric compound of claim 26, wherein the sugar surrogate is any of morpholino, modified morpholino, PNA, THP, and F-HNA.
 28. The oligomeric compound of any of claims 1-27, wherein the modified oligonucleotide is a gapmer.
 29. The oligomeric compound of any of claims 1-28, wherein the modified oligonucleotide comprises: a 5′-region consisting of 1-6 linked 5′-region nucleosides; a central region consisting of 6-10 linked central region nucleosides; and a 3′-region consisting of 1-6 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a modified sugar moiety and at least six of the central region nucleosides comprise a 2′-β-D-deoxyribosyl sugar moiety.
 30. The oligomeric compound of any of claims 1-28, wherein the modified oligonucleotide comprises: a 5′-region consisting of 1-6 linked 5′-region nucleosides; a central region consisting of 6-10 linked central region nucleosides; and a 3′-region consisting of 1-6 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a modified sugar moiety and each of the central region nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety.
 31. The oligomeric compound of claim 29, wherein the modified oligonucleotide comprises: a 5′-region consisting of 5 linked 5′-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3′-region consisting of 5 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and at least six of the central region nucleosides comprise a 2′-β-D-deoxyribosyl sugar moiety.
 32. The oligomeric compound of claim 30, wherein the modified oligonucleotide comprises: a 5′-region consisting of 5 linked 5′-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3′-region consisting of 5 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and each of the central region nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety.
 33. The oligomeric compound of claim 29, wherein the modified oligonucleotide comprises: a 5′-region consisting of 6 linked 5′-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3′-region consisting of 4 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and at least six of the central region nucleosides comprise a 2′-β-D-deoxyribosyl sugar moiety.
 34. The oligomeric compound of claim 30, wherein the modified oligonucleotide comprises: a 5′-region consisting of 6 linked 5′-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3′-region consisting of 4 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and each of the central region nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety.
 35. The oligomeric compound of claim 29, wherein the modified oligonucleotide comprises: a 5′-region consisting of 4 linked 5′-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3′-region consisting of 6 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and at least six of the central region nucleosides comprise a 2′-β-D-deoxyribosyl sugar moiety.
 36. The oligomeric compound of claim 30, wherein the modified oligonucleotide comprises: a 5′-region consisting of 4 linked 5′-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3′-region consisting of 6 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and each of the central region nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety.
 37. The oligomeric compound of claim 29, wherein the modified oligonucleotide comprises: a 5′-region consisting of 4 linked 5′-region nucleosides; a central region consisting of 8 linked central region nucleosides; and a 3′-region consisting of 6 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and at least six of the central region nucleosides comprise a 2′-β-D-deoxyribosyl sugar moiety.
 38. The oligomeric compound of claim 30, wherein the modified oligonucleotide comprises: a 5′-region consisting of 4 linked 5′-region nucleosides; a central region consisting of 8 linked central region nucleosides; and a 3′-region consisting of 6 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and each of the central region nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety.
 39. The oligomeric compound of claim 29, wherein the modified oligonucleotide comprises: a 5′-region consisting of 6 linked 5′-region nucleosides; a central region consisting of 8 linked central region nucleosides; and a 3′-region consisting of 4 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and at least six of the central region nucleosides comprise a 2′-β-D-deoxyribosyl sugar moiety.
 40. The oligomeric compound of claim 30, wherein the modified oligonucleotide comprises: a 5′-region consisting of 6 linked 5′-region nucleosides; a central region consisting of 8 linked central region nucleosides; and a 3′-region consisting of 4 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and each of the central region nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety.
 41. The oligomeric compound of claim 29, wherein the modified oligonucleotide comprises: a 5′-region consisting of 5 linked 5′-region nucleosides; a central region consisting of 8 linked central region nucleosides; and a 3′-region consisting of 5 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and at least six of the central region nucleosides comprise a 2′-β-D-deoxyribosyl sugar moiety.
 42. The oligomeric compound of claim 30, wherein the modified oligonucleotide comprises: a 5′-region consisting of 5 linked 5′-region nucleosides; a central region consisting of 8 linked central region nucleosides; and a 3′-region consisting of 5 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and each of the central region nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety.
 43. The oligomeric compound of claim 29 or claim 30, wherein the 5′-region or the 3′-region comprises at least one bicyclic nucleoside.
 44. The oligomeric compound of claim 29 or claim 30, wherein the 5′-region or the 3′-region comprises at least one nucleoside that is not a bicyclic nucleoside.
 45. The oligomeric compound of claim 29 or claim 30, wherein the 5′-region or the 3′-region comprises at least one nucleoside that is not a LNA nucleoside.
 46. The oligomeric compound of any of claims 1-45, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.
 47. The oligomeric compound of claim 46, wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.
 48. The oligomeric compound of claim 46 or claim 47, wherein each internucleoside linkage is a modified internucleoside linkage.
 49. The oligomeric compound of claim 48, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
 50. The oligomeric compound of any of claims 46-47, wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphodiester internucleoside linkage.
 51. The oligomeric compound of any of claims 1-46, wherein each internucleoside linkage of the modified oligonucleotide is independently selected from a phosphodiester or a phosphorothioate internucleoside linkage.
 52. The oligomeric compound of any of claims 1-47 or 50-51, wherein at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 internucleoside linkages of the modified oligonucleotide are phosphorothioate internucleoside linkages.
 53. The oligomeric compound of claim 46, wherein the internucleoside linkage motif of the modified oligonucleotide is selected from soooossssssssssooss, sooooossssssssssoss, sooossssssssssoooss, soosssssssssoooss, soooosssssssssoss, and sooosssssssssooss, wherein s=a phosphorothioate internucleoside linkage and o=a phosphodiester internucleoside linkage.
 54. The oligomeric compound of any of claims 1-53, wherein the modified oligonucleotide comprises at least one modified nucleobase.
 55. The oligomeric compound of claim 54, wherein the modified nucleobase is a 5-methyl cytosine.
 56. The oligomeric compound of any of claims 1-55, wherein the oligomeric compound is capable of reducing the amount of SCN2A RNA in vitro by at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% when administered according to a standard in vitro assay.
 57. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: (SEQ ID NO: 2493) G_(es) ^(m)C_(eo)A_(eo)T_(eo)A_(eo)A_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) T_(ds)T_(ds)A_(ds)T_(ds)A_(eo) ^(m)C_(eo)A_(es)A_(es)A_(e),

wherein: A=an adenine nucleobase, ^(m)C=a 5-methyl cytosine nucleobase, G=a guanine nucleobase, T=a thymine nucleobase, e=a 2′-MOE sugar moiety, d=a 2′-β-D-deoxyribosyl sugar moiety, s=a phosphorothioate internucleoside linkage, and o=a phosphodiester internucleoside linkage.
 58. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: (SEQ ID NO: 2514) ^(m)C_(es)A_(eo) ^(m)C_(eo)G_(eo)A_(eo) ^(m)C_(eo)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds) T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(eo) ^(m)C_(es)A_(es) ^(m)C_(e),

wherein: A=an adenine nucleobase, ^(m)C=a 5-methyl cytosine nucleobase, G=a guanine nucleobase, T=a thymine nucleobase, e=a 2′-MOE sugar moiety, d=a 2′-β-D-deoxyribosyl sugar moiety, s=a phosphorothioate internucleoside linkage, and o=a phosphodiester internucleoside linkage.
 59. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: (SEQ ID NO: 2510) ^(m)C_(es) ^(m)C_(eo)A_(eo) ^(m)C_(eo)G_(eo)A_(eo) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds) T_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(eo)A_(es) ^(m)C_(es)A_(e),

wherein: A=an adenine nucleobase, ^(m)C=a 5-methyl cytosine nucleobase, G=a guanine nucleobase, T=a thymine nucleobase, e=a 2′-MOE sugar moiety, d=a 2′-β-D-deoxyribosyl sugar moiety, s=a phosphorothioate internucleoside linkage, and o=a phosphodiester internucleoside linkage.
 60. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: (SEQ ID NO: 2487) T_(es) ^(m)C_(eo)T_(eo)G_(eo) ^(m)C_(eo)A_(eo)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(eo)T_(es)A_(es) ^(m)C_(e),

wherein: A=an adenine nucleobase, ^(m)C=a 5-methyl cytosine nucleobase, G=a guanine nucleobase, T=a thymine nucleobase, e=a 2′-MOE sugar moiety, d=a 2′-β-D-deoxyribosyl sugar moiety, s=a phosphorothioate internucleoside linkage, and o=a phosphodiester internucleoside linkage.
 61. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: (SEQ ID NO: 2493) G_(es) ^(m)C_(eo)A_(eo)T_(eo)A_(eo)A_(eo)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(eo)A_(es)A_(es)A_(e),

wherein: A=an adenine nucleobase, ^(m)C=a 5-methyl cytosine nucleobase, G=a guanine nucleobase, T=a thymine nucleobase, e=a 2′-MOE sugar moiety, d=a 2′-β-D-deoxyribosyl sugar moiety, s=a phosphorothioate internucleoside linkage, and o=a phosphodiester internucleoside linkage.
 62. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: GT (SEQ ID NO: 2534) ^(m)C_(es)T_(eo)G_(eo) ^(m)C_(eo)A_(es)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(eo)T_(eo)A_(es)T_(es)A_(e),

wherein: A=an adenine nucleobase, ^(m)C=a 5-methyl cytosine nucleobase, G=a guanine nucleobase, T=a thymine nucleobase, e=a 2′-MOE sugar moiety, d=a 2′-β-D-deoxyribosyl sugar moiety, s=a phosphorothioate internucleoside linkage, and o=a phosphodiester internucleoside linkage.
 63. The oligomeric compound of any of claims 1-62 wherein the oligomeric compound is a singled-stranded oligomeric compound.
 64. The oligomeric compound of any of claims 1-63, wherein the modified oligonucleotide of the oligomeric compound is a salt, and wherein the salt is a sodium salt or a potassium salt.
 65. The oligomeric compound of any of claims 1-64, consisting of the modified oligonucleotide.
 66. The oligomeric compound of any of claims 1-62, wherein the modified oligonucleotide is an RNAi compound.
 67. The oligomeric compound of any of claims 1-66, further comprising a conjugate group.
 68. The oligomeric compound of claim 67, wherein the conjugate group comprises a conjugate moiety and a conjugate linker.
 69. The oligomeric compound of claim 68, wherein the conjugate group comprises a GalNAc cluster comprising 1-3 GalNAc ligands.
 70. The oligomeric compound of claim 68, wherein the conjugate linker consists of a single bond.
 71. The oligomeric compound of claim 68, wherein the conjugate linker is cleavable.
 72. The oligomeric compound of claim 68, wherein the conjugate linker comprises 1-3 linker-nucleosides.
 73. The oligomeric compound of any of claims 67-72, wherein the conjugate group is attached to the modified oligonucleotide at the 5′-end of the modified oligonucleotide.
 74. The oligomeric compound of any of claims 67-72, wherein the conjugate group is attached to the modified oligonucleotide at the 3′-end of the modified oligonucleotide.
 75. The oligomeric compound of any of claims 1-74 further comprising a terminal group.
 76. The oligomeric compound of any of claims 1-71 or 73-75, wherein the oligomeric compound does not comprise linker-nucleosides.
 77. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.
 78. The modified oligonucleotide of claim 77, which is the sodium salt or the potassium salt.
 79. A modified oligonucleotide according to the following chemical structure:


80. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.
 81. The modified oligonucleotide of claim 80, which is the sodium salt or the potassium salt.
 82. A modified oligonucleotide according to the following chemical structure:


83. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.
 84. The modified oligonucleotide of claim 83, which is the sodium salt or the potassium salt.
 85. A modified oligonucleotide according to the following chemical structure:


86. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.
 87. The modified oligonucleotide of claim 86, which is the sodium salt or the potassium salt.
 88. A modified oligonucleotide according to the following chemical structure:


89. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.
 90. The modified oligonucleotide of claim 89, which is the sodium salt or the potassium salt.
 91. A modified oligonucleotide according to the following chemical structure:


92. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.
 93. The modified oligonucleotide of claim 92, which is the sodium salt or the potassium salt.
 94. A modified oligonucleotide according to the following chemical structure:


95. A chirally enriched population of oligomeric compounds of any of claim 1-76 or modified oligonucleotides of any of claims 77-94, wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration.
 96. The chirally enriched population of claim 95, wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Sp) configuration.
 97. The chirally enriched population of claim 95, wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Rp) configuration.
 98. The chirally enriched population of claim 95, wherein the population is enriched for modified oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage.
 99. The chirally enriched population of claim 98, wherein the population is enriched for modified oligonucleotides having the (Sp) configuration at each phosphorothioate internucleoside linkage or for modified oligonucleotides having the (Rp) configuration at each phosphorothioate internucleoside linkage.
 100. The chirally enriched population of claim 98, wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at one particular phosphorothioate internucleoside linkage and the (Sp) configuration at each of the remaining phosphorothioate internucleoside linkages.
 101. The chirally enriched population of claim 98, wherein the population is enriched for modified oligonucleotides having at least 3 contiguous phosphorothioate internucleoside linkages in the Sp, Sp, and Rp configurations, in the 5′ to 3′ direction.
 102. A population of oligomeric compounds of any of claims 1-76 or modified oligonucleotides of any of claims 77-94, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.
 103. An oligomeric duplex, comprising a first oligomeric compound and a second oligomeric compound comprising a second modified oligonucleotide, wherein the first oligomeric compound is an oligomeric compound of any of claims 1-76.
 104. The oligomeric duplex of claim 103, wherein the second oligomeric compound comprises a second modified oligonucleotide consisting of 8 to 80 linked nucleosides, and wherein the nucleobase sequence of the second modified oligonucleotide comprises a complementary region of at least 8 nucleobases that is at least 90% complementary to an equal length portion of the first modified oligonucleotide.
 105. An antisense agent comprising an antisense compound, wherein the antisense compound is an oligomeric compound of any of claims 1-76 or a modified oligonucleotide of any of claims 77-94.
 106. The antisense agent of claim 105, wherein the antisense agent is an oligomeric duplex of claim 103 or claim
 104. 107. The antisense agent of claim 105 or claim 106, wherein the antisense agent is: i. an RNase H agent capable of reducing the amount of SCN2A nucleic acid through the activation of RNase H; or ii. an RNAi agent capable of reducing the amount of SCN2A nucleic acid through the activation of RISC/Ago2.
 108. A pharmaceutical composition comprising an oligomeric compound of any of claims 1-76, a modified oligonucleotide of any of claims 77-94, a population of any of claims 95-102, an oligomeric duplex of claim 103 or claim 104, or an antisense agent of any of claims 105-107, and a pharmaceutically acceptable diluent or carrier.
 109. The pharmaceutical composition of claim 108, comprising a pharmaceutically acceptable diluent and wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid (aCSF) or phosphate-buffered saline (PBS).
 110. The pharmaceutical composition of claim 109, wherein the pharmaceutical composition consists essentially of the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, or the antisense agent, and aCSF.
 111. The pharmaceutical composition of claim 109, wherein the pharmaceutical composition consists essentially of the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, or the antisense agent, and PBS.
 112. A pharmaceutical composition comprising a modified oligonucleotide of any of claims 77-94 and a pharmaceutically acceptable diluent.
 113. The pharmaceutical composition of claim 112, wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid (aCSF) or phosphate-buffered saline (PBS).
 114. The pharmaceutical composition of claim 113, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and aCSF.
 115. The pharmaceutical composition of claim 113, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.
 116. A method comprising administering to a subject an oligomeric compound of any of claims 1-76, a modified oligonucleotide of any of claims 77-94, a population of any of claims 95-102, an oligomeric duplex of claim 103 or claim 104, an antisense agent of any of claims 105-107, or a pharmaceutical composition of any of claims 108-115.
 117. A method of treating a disease or disorder associated with a voltage-gated sodium channel protein, comprising administering to a subject having or at risk for developing the disease or disorder associated with a voltage-gated sodium channel protein a therapeutically effective amount of an oligomeric compound of any of claims 1-76, a modified oligonucleotide of any of claims 77-94, a population of any of claims 95-102, an oligomeric duplex of claim 103 or claim 104, an antisense agent of any of claims 105-107, or a pharmaceutical composition of any of claims 108-115, thereby treating the disease or disorder associated with a voltage-gated sodium channel protein.
 118. A method of reducing the amount of SCN2A protein in the CSF of a subject having or at risk for developing a disease or disorder associated with a voltage-gated sodium channel protein a therapeutically effective amount of an oligomeric compound of any of claims 1-76, a modified oligonucleotide of any of claims 77-94, a population of any of claims 95-102, an oligomeric duplex of claim 103 or claim 104, an antisense agent of any of claims 105-107, or a pharmaceutical composition of any of claims 108-115, thereby reducing the amount of SCN2A protein in the CSF.
 119. The method of claim 117 or claim 118, wherein the disease or disorder is a neurodevelopmental disease.
 120. The method of claim 117 or claim 118, wherein the disease or disorder is associated with SCN1A or SCN2A.
 121. A method of treating a disease or disorder associated with SCN2A, comprising administering to an subject having or at risk for developing a disease or disorder associated with SCN2A a therapeutically effective amount of an oligomeric compound of any of claims 1-76, a modified oligonucleotide of any of claims 77-94, a population of any of claims 95-102, an oligomeric duplex of claim 103 or claim 104, an antisense agent of any of claims 105-107, or a pharmaceutical composition of any of claims 108-115, thereby treating the disease or disorder associated with SCN2A.
 122. The method of claim 121, wherein the disease or disorder associated with SCN2A is a Developmental and Epileptic Encephalopathy, an intellectual disability, or an autism spectrum disorder.
 123. The method of claim 122, wherein the Developmental and Epileptic Encephalopathy is any of Early Seizure Onset Epileptic Encephalopathy (EE), Late Seizure Onset Epileptic Encephalopathy, or Benign Familial Neonatal-Infantile Seizures.
 124. The method of claim 121, wherein the disease or disorder associated with SCN2A is any of Ohtahara Syndrome, epilepsy with migrating focal seizures of infancy, West Syndrome, Lennon-Gastaut Syndrome; Dravet Syndrome; Idiopathic/Generic Generalized Epilepsies, Temporal Lobe Epilepsy, Myoclonic Astatic Epilepsy, Migrating Partial Epilepsy of Infancy, or familial hemiplegic migraines.
 125. The method of any of claims 118-120, wherein the disease or disorder is associated with SCN1A.
 126. The method of claim 125, wherein the disease or disorder associated with SCN1A is a Developmental and Epileptic Encephalopathy.
 127. The method of claim 125 or claim 126, wherein the Developmental and Epileptic Encephalopathy is Dravet Syndrome.
 128. The method of claim 126 or claim 127, wherein the Developmental and Epileptic Encephalopathy is any of Ohtahara Syndrome, epilepsy with migrating focal seizures of infancy, West Syndrome, Lennon-Gastaut Syndrome; Dravet Syndrome; Idiopathic/Generic Generalized Epilepsies, Temporal Lobe Epilepsy, Myoclonic Astatic Epilepsy, Migrating Partial Epilepsy of Infancy, or familial hemiplegic migraines.
 129. The method of any of claims 117-128, wherein at least one symptom or hallmark of the disease or disorder is ameliorated.
 130. The method of claim 129, wherein the symptom or hallmark is seizures.
 131. The method of any of claim 130, wherein the seizures are any of focal, clonic, tonic, generalized tonic and clonic, convulsive, myoclonic, absence, or obtundation status.
 132. The method of claim 130, wherein the seizures are any of focal, clonic, tonic, or generalized tonic.
 133. The method of claim 129, wherein the symptom or hallmark is any of seizures, hypotonia, sensory integration disorders, motor dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, visual dysfunctions, delayed language and speech, gastrointestinal disorders, neurodevelopmental delays, or sudden unexpected death in epilepsy.
 134. The method of claim 129, wherein the symptom or hallmark is any of motor development delays, delayed social and language milestones, repetitive actions, uncoordinated oral movements, gastrointestinal disoders, sleep problems, or seizures.
 135. The method of any of claims 130-134, wherein the seizures are frequent or prolonged.
 136. The method of any of claims 116-135 wherein administering the modified oligonucleotide reduces seizures, sensory integration disorders, motor dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, visual dysfunctions, delayed language and speech, gastrointestinal disorders, neurodevelopmental delays, motor development delays, delayed social milestones, repetitive actions, uncoordinated oral movements, or sleep problems, hypotonia, nystagmus, optic atrophy, respiratory distress, motor delays, cognitive dysfunction, speech dysfunction, spasticity, ataxia, seizures, or choreiform movements, or delays death in the subject.
 137. The method of any of claims 116-136, wherein the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, the antisense agent, or the pharmaceutical composition is administered to the central nervous system or systemically.
 138. The method of any of claims 116-136, wherein the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, the antisense agent, or the pharmaceutical composition is administered to the central nervous system and systemically.
 139. The method of any of claims 116-131, wherein the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, the antisense agent, or the pharmaceutical composition is administered by any of intrathecally, systemically, subcutaneously, or intramuscularly.
 140. The method of any of claims 116-139, wherein the subject is human.
 141. A method of reducing the amount of SCN2A RNA in a cell comprising contacting the cell with an oligomeric compound of any of claims 1-76, a modified oligonucleotide of any of claims 77-94, a population of any of claims 95-102, an oligomeric duplex of claim 103 or claim 104, an antisense agent of any of claims 105-107, or a pharmaceutical composition of any of claims 108-115, thereby reducing the amount of SCN2A RNA in the cell.
 142. A method of reducing the amount of SCN2A protein in a cell comprising contacting the cell with an oligomeric compound of any of claims 1-76, a modified oligonucleotide of any of claims 77-94, a population of any of claims 95-102, an oligomeric duplex of claim 103 or claim 104, an antisense agent of any of claims 105-107, or a pharmaceutical composition of any of claims 108-115, thereby reducing the amount of SCN2A protein in the cell.
 143. The method of claim 141 or claim 142, wherein the cell is a cortical cell, a hippocampal cell, or a spinal cord cell.
 144. The method of any of claims 141-143, wherein the cell is in an animal.
 145. The method of any of claims 141-144, wherein the cell is a human cell.
 146. Use of an oligomeric compound of any of claims 1-76, a modified oligonucleotide of any of claims 77-94, a population of any of claims 95-102, an oligomeric duplex of claim 103 or claim 104, an antisense agent of any of claims 105-107, or a pharmaceutical composition of any of claims 108-115 for reducing SCN2A expression in a cell.
 147. The use of claim 146, wherein the level of SCN2A RNA in the cell is reduced.
 148. The use of claim 146 or claim 147, wherein the level of SCN2A protein in the cell is reduced.
 149. The use of any of claims 146-148, wherein the cell is a corical cell, a hippocampal cell, or a spinal cord cell. 